CHEM10100 Lecture Notes1.pdf

Aspects of Medicinal Chemistry and Chemical Biology CHEM10100 Dr Elaine O’Reilly [email protected] Office 3.11, Science South Overview of EOR’s Lectures A brief history of the pharmaceutical industry and the earliest medicinal drugs An o...

Aspects of Medicinal Chemistry and Chemical Biology CHEM10100 Dr Elaine O’Reilly [email protected] Office 3.11, Science South Overview of EOR’s Lectures A brief history of the pharmaceutical industry and the earliest medicinal drugs An overview of the drug discovery and development process Drug targets – including a detailed look at some examples What makes a good drug – drug properties Ø including: pKa, stereochemistry, lipophilicity, H-bonding, electronegativity Synthesis of lead compounds in industry – chemistry; purification; analysis Drug metabolism It is NOT necessary for you to buy any of these texts I will upload any useful literature and links on Brightspace Learning Outcomes for EOR’s Lectures Ø Understand key drug targets Ø Predict various drug properties and how they might affect biological activity Ø Identify important functionality and predict likely interactions with drug targets All this knowledge is underpinned by understanding the interactions and chemistry that can take place with drug molecules Ø An important part of a chemist's skill-set is drawing molecules Ø Although I will use PowerPoint, we will also do some interactive problems and you will be required to draw structures (anyone requiring full set of notes, due to specific accommodations, please contact me) A few things to think about… Ø Can you define a Drug? Ø What do you think is the most important drug (or drug class)? Why? Ø What is the difference between pharmaceutical drugs and drugs of abuse? Are there good and bad drugs? Early Pharmaceuticals The first medicinal drugs came from natural sources – herbs, plants, roots, vines and fungi Nature provides a rich source of biologically active compounds (often secondary metabolites), which can serve as toxins for self-defense The first synthetic drug, chloral hydrate, was discovered in 1896 and introduced as a sedative-hypnotic The first pharmaceutical companies were spin-offs from the textiles and synthetic dye industry Quinine Morphine anti-malarial Pain treatment Drug Test. Analysis. 2011, 3, 337-344 Early Pharmaceuticals The use of biologically active compounds directly from their natural sources presents many challenges – can you suggest some challenges? Morphine was first isolated in it’s pure form by Friedrich Willhelm Sertüner in the early 1800’s Its isolation can be considered the single most important discovery in modern medicine – more so than penicillin perhaps. The discovery demonstrated that a drug could be extracted, purified and measured into a dose. It also unlocked a wealth of other biologically active compounds that were hidden in plants Morphine Pain treatment Dr Michael Mosely https://www.youtube.com/watch?v=2hTZNDyLPLk Early Pharmaceuticals Nature’s medicine cabinet was suddenly blown wide open!!! A class of compounds, called alkaloids, were some of the first bioactive compounds isolated from plants and are responsible for the biological activity of the natural materials. Morphine itself is an alkaloid (as is quinine) and there are an enormous number of structurally related and distinct alkaloids that exist in plants and animals Morphine Pain treatment Dr Michael Mosely https://www.youtube.com/watch?v=2hTZNDyLPLk Early Pharmaceuticals Ø Chloroform was one of the first synthetic drugs used. It was employed as an anesthetic Ø Demonstrated that the volatile liquid could help with pain (including childbirth) and it was an important general anesthetic for many years Chloroform Drug Test. Analysis. 2011, 3, 337-344  Early Pharmaceuticals Ø The entire pharmaceutical industry can be traced back to the manufacture of textiles and synthetic dyes Ø The Friedrich Bayer Company was one of the first to show an interest in pharmaceuticals. The black sticky mess (tar) remaining after distillation of coal under vacuum provided a rich source of aromatic compounds Ø Acetanilide was the first synthetic antipyretic drug marketed (1886), and became known as Antifebrin® (fever-reducing) Ø The success of this drug prompted the Bayer Company to search for other drugs in their waste products and p-nitrophenol was identified, which was easily converted into the ethyl ester derivative of acetanilide, to give phenacetin® ting Ø A derivative of phenacetin prepared around the same time was N-acetyl-p-aminophenol (paracetamol) sis A. W. Jones NH O NH O CH3 CH3 HO H3 C O OH Paracetamol (1887) Phenacetin (1887) NH O O OH O2N CH3 O O para-nitrophenol CH3 Acetanilide (1886) Aspirin (1899) structures of early analgesic and anti-pyretic drugs. Can you name all the functional groups in these molecules? Drug Test. Analysis. 2011, 3, 337-344 Impact of drug discovery 1940s onwards Antibiotics Revolutionized the way infectious diseases are treated Anti-HIV Death rates due to AIDs were slashed Drugs Reduction in ‘bad’ cholesterol leading to reduction in Statins cardiovascular disease Drug discovery is simple, right? Ø Identify patients that have a disease Ø Make a compound that has the desired biological activity Ø Give it to the patients – find the efficacious dose Ø Sell it! So why does the process take so long and cost so much? Choose a part of Find a drug that Choose a Test it in patients the disease to should treat the disease to see if it works target disease 10 – 15 years Biology/pharmacology discovery stage Choose a part of Find a drug that Test it in patients the disease to should treat the to see if it works target disease Drug target Drug target selection validation 2 – 3 years Medicinal chemistry discovery stage Choose a part of Find a drug that Test it in patients the disease to should treat the to see if it works target disease Chemical lead Development Lead optimization discovery candidate 2 – 5 years Safety, efficacy, approval stage Choose a part of Find a drug that Test it in patients the disease to should treat the to see if it works target disease Pre-clinical Clinical development Regulatory development (efficacy) approval (safety) Up to 10 years Here is the problem … Ø Potential drug candidates have many properties Ø All must be good enough to make the candidate a successful drug Ø Many candidates are rejected (it’s better if this happens early in the discovery process!) Ø How can we design all the right properties into just one molecule?? Ø And what are the right properties? Let’s consider the properties that a drug must have to reach its target and have the desired effect Property 1 Property 2 Property 3 these can affect bioavailability; metabolism; clearance; toxicity and pharmacology Ø One of the most important features of a drug is that it binds to its target Ø Later, we will focus on some interactions that lead to binding Drug Targets Ø A drug target is an area of the disease where a drug can intervene Ø The nature of the target depends on the disease Human (Cancer, autoimmune …) Infection: Fungal Bacterial Viral Ø An ideal drug should target the disease and not have a significant effect anywhere else. Ø This is often not the case! Can you think of some examples? Do you recognize this infamous pair of drug enantiomers? Question: why do natural products often make good leads?  Drug Targets Ø Drug targets are large molecules – macromolecules Ø Drugs are generally much smaller than their targets Ø They interact with their targets by binding to binding sites Ø Binding sites are typically hydrophobic pockets on the surface of macromolecules or buried within the protein (for enzymes) Ø Binding interactions typically involve intermolecular ‘bonds’ Ø Most drugs are in equilibrium between being bound and unbound to their target Ø Functional groups on the drug are involved in binding interactions and these are called binding groups Ø Specific regions within the binding sites that are involved in these interactions are called binding regions https://www.chem.uwec.edu/Chem491_W09/Topic1Overview.pdf Drug Targets There are a few common drug targets: Ø Proteins G-Protein coupled receptors Enzymes Ion channels Structural proteins Transport proteins Nuclear receptors Ø Lipids Cell membrane lipids Ø Nucleic acids DNA and RNA Ø Carbohydrates Arterioscler. Thromb. Vasc. Biol. 2009, 29, 650-656. Call surface carbohydrates Antigens and recognition molecules Ø We will look at a few of these in more detail  Drug Targets: Cell Structure Ø Human, animal and plant cells are eukaryotic Ø Nucleus contains the genetic blueprint (DNA) Ø The fluid contents of the cell are known as the cytoplasm Ø Structures within the cell are known as organelles Ø Mitochondria are the source of energy production Ø Ribosomes are the cell’s protein factories Ø Rough endoplasmic reticulum is the location for protein synthesis Life is made up of cells, and so drugs must act on cells. A mammalian cell has a boundary wall, called a cell membrane, which encloses the cell contents – the cytoplasm. https://www.chem.uwec.edu/Chem491_W09/Topic1Overview.pdf https://www.microscopemaster.com/organelles.html  Cell Membrane Cell Membrane ll Membrane CH2CH2NMe3 Polar O Proteins Head Group Polar Head O P O Exterior Group O High [Na+] CH2 CH CH2 O O O O Hydrophobic Tails Phospholipid Bilayer Hydrophobic Tails Interior High [K+] Ø The cell membrane is made up of a phospholipid bilayer Ø The hydrophobic tails interact with each other by van der Waals interactions and are hidden from the aqueous media Ø The polar heads interact with water at the inner and outer surfaces of the membrane Ø The cell membrane provides a hydrophobic barrier around the cell, preventing the passage of water and polar molecules Ø Proteins are present in the cell membrane and can act as ion channels and carrier proteins Drug Targets- Enzymes Ø Enzymes are usually proteins (not all proteins are enzymes) that possess catalytic activity (RNA can also be catalytically active) Ø The part of the enzyme tertiary structure that is responsible for the catalytic activity is called the “active site” of the enzyme Ø The active site is typically a cleft or cavity that contains an array of amino acid side chains, which bind the substrate/cofactor and carry out the enzymatic reaction Ø Many enzymes also use cofactors/coenzymes, which are necessary for catalysis Ø An important feature of enzymes is their high substrate specificity and this is due to a series of non-covalent enzyme-substrate interactions: Electrostatic Hydrogen bonding Non-polar (Van der Waals) interactions We will discuss these in detail! Hydrophobic Ø The chiral active site is often naturally able to bind one enantiomer selectively Drug Targets- Enzymes Primary Structure – Amino Acids Primary structure is the amino acid sequence and location of any disulfides The side chains of the AA’s in enzymes (or other protein targets) are available to interact with any drug molecules Drug Targets- Enzymes Primary Structure – Peptide bond Secondary structure refers to the spatial arrangement of amino acid residues that are near one another in the linear sequence Ø Polypeptide chains can fold into regularly repeating structures Ø α-helices and β-sheets (among others) Amino Acids – the Protein Alphabet Problem: amino acids make up all protein targets and so the interactions of their side chains are extremely important. Select amino acids that can get involved in: H-bonding, van der Waals and electrostatic interactions To answer this question properly, draw in the lone pairs for all relevant functional groups. There will be many answers to some of the interactions, so view it as a good way to examine your knowledge Drug Targets- Enzymes Christian Anfinsen Shared the Nobel Prize Tertiary Structure in Chemistry in 1972 Tertiary structure refers to the spatial arrangement of amino acid residues that are far apart in space Ø Minimizing the number of hydrophobic side chains exposed to water is a major driving force in protein folding Ø Anfinsen denatured the protein so it unfolded Ribonuclease Ø When he removed the denaturing conditions the protein regained almost 100% of its original activity Ø How do peptides fold from polypeptide chain to folded protein? Randomly?? – too many possibilities!! Protein secondary structure (α-helices and β-sheets etc) is thought to assist protein folding Drug Targets- Enzymes Quaternary Structure Quaternary structure involves the clustering of several peptide or proteins Ø Individual chains can be identical or distinct Hemoglobin And of course, these primary, secondary, tertiary and quaternary structures apply to all proteins (but the catalytic activity associated with enzymes does not.) Drug Targets- Enzymes Ø Proteases are enzymes that cleave proteins and peptides Ø There are four main mechanistic classes: Ø Aspartyl, e.g. renin, HIV protease Ø Serine, e.g. thrombin, urokinase, trypsin Ø Cystein, e.g. cathepsin K, transglutaminase Ø Metalloproteases, e.g. matrix metalloproteases, angiotensin converting enzyme. Recall: peptide bonds join the amino acids together to form peptides, which fold into a protein (perhaps an enzyme) Ø An enzyme that cleaves these vital bonds will cause the protein to be modified and possibly inactivated Catalytic Mechanism of Serine Proteases Note the example shown is chymotrypsin, a 240 amino acid protein. However, the key AA residues and mechanism is conserved for serine proteases (but the residue numbers will change). Substrate binding We will come back and talk in more detail about the interactions involved in substrate binding Nucleophilic attack Note: You do not need to learn the details of this mechanism, but you should be able to predict the intermolecular interactions that might take place, if provided with the active site and the substrate Catalytic Mechanism of Serine Proteases Protonation Ester Hydrolysis Why enzymes are often so selective for a particular substrate? For example, minor modifications in the substrate (maybe an extra methyl group) could shut activity down because the substrate no longer binds. Catalytic Mechanism of Serine Proteases Note: This explanation is here for completeness and to challenge students who are interested. However, the details are beyond the scope and level of this module and you are not expected to know them. Substrate binding: the side-chain of the amino acid residue immediately before the scissile peptide bond can bind to the recognition site on the enzyme. Nucleophilic attack: Ser195 acts as a nucleophile. It is facilitated by His57, which abstracts a proton from Ser195. The result of this nucleophilic attack is a covalent bond between the side chain oxygen of Ser195 and the substrate. The negative charge that develops on the peptide carbonyl is stabilized by hydrogen bonds formed between two amide bonds along the peptide backbone (including the one formed with the amide bond of Ser195 – the diagram is just distorted for clarity and thus the Ser residue has moved relative to where it would be in the three dimensional protein structure). Protonation: His57 donates a proton to the amide nitrogen of the substrate, allowing the release of the C- terminal portion of the peptide as a free peptide. Ester hydrolysis: The final step is an attack by a water molecule on the ester bond between the substrate and Ser195 to release the second peptide product with a carboxyl group and regenerate the serine hydroxyl. Once the second peptide dissociates from the active site, the catalytic cycle can begin again. The life cycle of HIV and a look at some drug targets Watch this short video and see if you can identify some drug targets. Try to think about the nature of the target (is it an enzyme, a receptor etc.…). Look out for all the cases where interactions (H-bonding, van der Waals, electrostatic) are likely to be key to the mechanism https://www.youtube.com/watch?v=odRyv7V8LAE Target identification To find out where to intervene in a disease process, we need to understand the disease Target validation To establish if intervening at the target and if this has the desired effect, we need biological/chemical probes/tools Atripla is a combination of three drugs - Efavirenz/emtricitabine/tenofovir All three drugs target the HIV reverse transcriptase protein (enzyme) Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) Emtricitabine and Tenafovir are nucleoside reverse transcriptase inhibitors (NRTI) Drug Targets - Ion Channels Ø Ion channels control the passage of ions (Na+, K+, Ca2+) in/out of cells. There are voltage-gated and ligand-gated channels Ø Ligand-gated: allow the passage of ions in response to the binding of a chemical messenger, such as a neurotransmitter e.g. GABA, nicotinic Acetylcholine, NMDA receptors all have small polar compounds as endogenous ligands Ø Voltage-gated: also allow the passage of ions, but are activated by changes in the electrical membrane potential near the membrane. The opening and closing is triggered by a change in ion concentration and hence gradient change, between the two sides of the membrane Na+ channels important for nerve signal conduction Local anesthetics and anticonvulsants Cl Me Cl H NH2 N NEt2 Cl N O N Me N NH2 Lidocaine Lamotrigine local anaesthetic anticonvulsant (epilepsy) Ions depicted as red spheres Drug Targets - G-protein-coupled receptors Ø G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP) Ø These receptors act like an inbox for cellular messages – proteins, peptides, lipids, sugar, light energy Ø They inform the cell about the presence or absence of life-sustaining nutrients or energy Ø The diverse variety of molecules that interact with GPCRs and the array of functions that they perform make them valuable drug targets (diabetes) https://www.youtube.com/watch?v=lkEvLrlPj-U https://www.nature.com/scitable/topicpage/gpcr-14047471/ Drug Targets - G-protein-coupled receptors G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes. These cell surface receptors act like an inbox for messages in the form of light energy, peptides, lipids, sugars, and proteins. Such messages inform cells about the presence or absence of life-sustaining light or nutrients in their environment, or they convey information sent by other cells. GPCRs play a role in an incredible array of functions in the human body, and increased understanding of these receptors has greatly affected modern medicine. In fact, researchers estimate that between one-third and one-half of all marketed drugs act by binding to GPCRs. What Do GPCRs Look Like? GPCRs bind a tremendous variety of signalling molecules, yet they share a common architecture that has been conserved over the course of evolution. Many present-day eukaryotes — including animals, plants, fungi, and protozoa — rely on these receptors to receive information from their environment. For example, simple eukaryotes such as yeast have GPCRs that sense glucose and mating factors. Not surprisingly, GPCRs are involved in considerably more functions in multicellular organisms. Humans alone have nearly 1,000 different GPCRs, and each one is highly specific to a particular signal. GPCRs consist of a single polypeptide that is folded into a globular shape and embedded in a cell's plasma membrane. Seven segments of this molecule span the entire width of the membrane — explaining why GPCRs are sometimes called seven-transmembrane receptors — and the intervening portions loop both inside and outside the cell. The extracellular loops form part of the pockets at which signalling molecules bind to the GPCR. https://www.nature.com/scitable/topicpage/gpcr-14047471/ Drug Targets - Nuclear Receptors Ø Receptors that exist in the cell nuclei Ø Their role is to bind to DNA and regulate gene expression I Ø Metabolism, heart rate, development I O NH2 = HO I CO2H I Thyroxine I I O NH2 Binding Alters gene expression and HO I CO2H I therefore protein production Thyroxine DNA strand Thyroid hormone Altered metabolic rate Thyroid hormone receptor How Drugs Bind to Their Target Ø For a drug to have any effect on a target, it must form some type(s) of interaction(s) with it. These interactions are rarely covalent bonds, but rather (weaker) intermolecular interactions Ø Maybe it’s a good time to remind/inform ourselves of the difference between intermolecular and intramolecular Ø We will look at these interactions and touch on other important (entropic) factors Enthalpic factors Van de Waals; dipoles; charges; H-bonding – these are all intermolecular binding forces Entropic factors Water; conformation – extremely important factors  Strongest of the intermolecular bonds (20-40 kJ mol-1) Takes Intermolecular place between groups of opposite charge Interactions The strength of the ionic interaction is inversely proportional Electrostatic or ionic bonds to the distance between the two charged groups Ø These are the Stronger strongest ofinteractions occur the intermolecular in hydrophobic interactions (20-40 kJ molenvironments -1) Ø Take place between groups of opposite charge The strength of interaction drops off less rapidly with Ø Stronger interactions occur in hydrophobic environments distance Ø Stronger at longer than distances with other compared to otherforms of intermolecular interactions interactions Ø Often very important Ionic as the drug bonds areenters the binding the most site – almost important guides initial the drug molecule interactions as a in drug enters the binding site O Drug Drug NH3 O O H3N Target Target O https://www.chem.uwec.edu/Chem491_W09/Topic1Overview.pdf  der Waals interactions AIntermolecular hydrogen bondInteractions takes place between an electron deficient hydrogen ecular and bonding Hydrogen an electron rich heteroatom (N or O) bonding forces The electron deficient hydrogen is usually attached to a onds bonds Ø Vary in strength typically heteroatom (O or N) 5-30 kJ/mol (can be higher in rare cases )(compare C-C ~346 kJ/mol and I-I 153 kJ/mol) Ø Weaker than electrostatic (ionic/charged) but stronger than van der Waals The electron deficient hydrogen is called a hydrogen bond Ø A hydrogen bond takes place between an electron deficient hydrogen and an electron rich heteroatom (N or O) donor Ø The electron deficient hydrogen is usually attached to a heteroatom (O or N) Ø The The electronrich electron deficient hydrogen isis heteroatom called a hydrogen called bond donor a hydrogen bond Ø The electron rich heteroatom is called a hydrogen bond acceptor acceptor !- !+ !- !- Drug Y !+ !- H X The interaction can be either direction, i.e. the X H Y Target Target HBA or donor can be on the drug or the target Drug HBD HBA HBA HBD N HBA The lone pair must be available for H-bonding (every heteroatom e.g. N atom, will not have an available lone pair) H HBD X R https://www.chem.uwec.edu/Chem491_W09/Topic1Overview.pdf  Intermolecular Interactions Intermolecular bonding forces Hydrogen bonding Hydrogen bonds N HBA The interaction involves orbitals and is directional H Optimum orientation is where the X-H bond points directly HBD X R to the lone pair on Y such that the angle between X, H and Y The interaction involves orbitals and is directional is 180o The optimum orientation is where the X-H bond points directly to the lone pair on Y such that the angle between X, H and Y is 180∘ X H Y X H Y Hybridised 1s Hybridised orbital orbital orbital HBD HBA https://www.chem.uwec.edu/Chem491_W09/Topic1Overview.pdf Intermolecular Interactions Hydrogen bonding Strong hydrogen bond acceptors: carboxylate ion, phosphate ion, tertiary amine Moderate hydrogen bond acceptors: carboxylic acid, amide oxygen, ketone, ester, ether, alcohol Poor hydrogen bond acceptors: sulfur, fluorine, chlorine, aromatic ring, amide nitrogen, aromatic amine Good hydrogen bond donors: Quaternary ammonium ion Identifying important functional groups is very important, as is identifying which are HBAs and HBDs Let’s try to identify some! In-class problems Intermolecular Interactions Hydrogen bonding in Nature Watson-Crick base pairs Protein secondary structures D. Eisenberg, Proc. Natl. Acad. Sci. 2003, 100, 11270-11210 How Drugs Bind to Their Target Enthalpy Factors that favour binding Ø van de Waals’ interactions between molecules and atoms comprising: v London dispersion forces v Dipole – induced dipole interactions v Dipole – dipole interactions v Let’s look at one example.. Note: For now, just remember and consider van de Waals and don’t worry about the specific types. How Drugs Bind to Their Target van der Waals Interactions v London dispersion forces These are short range, relatively weak interactions but can be extremely important for binding Require close contact between drug and target CH3 CH3 H 3C CH3 𝛿 H 3C CH3 CH3 𝛿 CH3 𝛿 CH3 CH3 𝛿 H 3C CH3 H 3C CH3 CH3 CH3 https://www.zmescience.com/science/physics/direct-measurement-of-van-der-waals-force-made-for-the-first-time/ How Drugs Bind to Their Target van der Waals Interactions Let’s think a little more about van der Waals forces Problem: Explain the difference in boiling points between He and Ar gas Boiling point of He gas = -268.9 ℃ Boiling point of Ar gas = -185.8 ℃ https://sciencenotes.org/electronegativity-definition-and-trend/ How Drugs Bind to Their Target van der Waals Interactions Let’s think a little more about van der Waals forces Problem: Explain the difference in boiling points between butane and isobutane (draw out the molecules and take a look!) How Drugs Bind to Their Target Practice problem How might these functional groups interact? Cl HN O Drug Target with chlorophenyl group amide bond π-π & Charge- π Interactions HO Protein π system Drug Drug π system protonated amine HN H N CH3 CH3 H N Delocalised π-system O Tyrosine CF3 HN Histidine O Ø Amino acid side chains containing aromatic rings: Tryptophan, phenylalanine, tyrosine, histidine Ø All these amino acids can potentially get involved in π-interactions Amino Acids – the Protein Alphabet The side chains of the AA’s in enzymes (or other protein targets) are available to interact with any drug molecules Let’s pick out the amino acids that are likely to have 1) strong electrostatic interactions with a drug bearing a) a carboxylate anion and b) an amine a) 𝚷-charge interactions with a drug bearing a protonated amine Class Exercise Design a drug, based on this pharmacophore, that will bind strongly to this binding pocket. Please be as inventive as you like and try to incorporate as many of the concepts that you have learned as you can (intermolecular interactions, importance of key functional groups, conformational restriction …). The drug does not have to interact with every residue but include as many as you can. Glutamic acid Try and incorporate lots of: electrostatic interactions O- Leucine pi-pi stacking interactions Tyrosine O Glutamic acid van der Waals interactions H-bonding interactions OH O- label the HBDs and HBAs O Phenylalanine NH3 O O Aspartic acid Lysine HN Tryptophan There is no right or wrong answer, because I have invented this binding pocket myself! Class Exercise Glutamic acid O- Leucine Tyrosine O Glutamic acid OH O- O Phenylalanine NH3 O O Aspartic acid Lysine HN Tryptophan Structure Activity Relationships (SARs) Over the next two lectures, we will explore the concept of SAR and examine a number of common functional groups (FGs) found in drug molecules Structure Activity Relationships (SARs) Ø What ingredients to I really need to make this cake? Ø Would removing one or two really matter? Ø Would adding more of some make it nicer?  Structure Activity Relationships (SARs) Ø Do I need all these weapons to be an effective fighter? Ø What on earth are all these keys for??? https://www.enworld.org/threads/too-many-weapons.479630/ (image credit) Structure Activity Relationships (SARs) Structure Activity Relationship (SAR) studies aim to understand the role that each functional group or structural features in a molecule plays in its ability to bind to the drug target SAR is not about optimizing (not at that point), but a way to study how the drug binds SAR studies are important prior to beginning any drug optimization – how can you start optimizing a molecule if you don’t know how it interacts with the target The idea centers around probing the role of various functional groups Structure Activity Relationships (SARs) Let’s use the calcium channel blocker, Glipin, as an example OH Potential H-bonding groups OH Me OH Potential van der waals binding groups Me OH Me Potential ionic binding groups Me N Me N H Me H OH OH OMe Me OH Me OH Me OMe Me Me N Me Me N H H N H Me Is the alkene necessary? H Structure Activity Relationships (SARs) The binding role of common functional groups Aromatic groups Change to a cyclohexane analogue. What effect might this have on binding? R cyclohexane R R analogue Good interaction R H H Flat hydrophobic poor interaction binding region Flat hydrophobic binding region What other interaction can the aromatic ring get involved in that the cyclohexane analogue cannot? Ø Modification of this nature will depend on how easy it is to access these analogues Structure Activity Relationships (SARs) The binding role of common functional groups Alkenes Alkene to alkane. What effect might this have on binding? Bulky Flat R R R R R R R R H H Hydrophobic Hydrophobic binding region binding region Ø Alkenes are planar and hydrophobic (like aromatic rings), so they can interact with hydrophobic regions of the binding site through van der Waals interactions Ø It’s worth testing the saturated alkyl group (the alkane) because it’s bulkier and cannot approach the relevant region of the binding site as easily Ø Often quite easy to reduce an alkene to an alkene Structure Activity Relationships (SARs) The binding role of common functional groups Ketones and aldehydes Carbonyl to alcohol. What effect might this have on binding? Carbonyl Alcohol R δ+ δ- O H O R R R dipole-dipole H interaction Binding region Binding region Ø The ketone is planar and can interact through hydrogen bonding (lone pairs on oxygen) Ø A dipole-dipole interaction with the target is also possible with ketone and alcohol Ø Significant geometry change from ketone to alcohol (planar to tetrahedral) Ø It is straightforward to reduce a ketone or aldehyde to an alcohol Ø Aldehyde functional groups (FGs) are rare in drug compounds, because the group is very reactive Structure Activity Relationships (SARs) The binding role of common functional groups Amines Ø Amines are very important FGS in drug molecules Ø Can act as HBDs and HBAs Ø Amines can be primary, secondary or tertiary and each can form different number of H-bonding interactions as the HBD Ø Aromatic and heteroaromatic amines can only act as HBDs, as the lone pair interacts with the (hetero)aromatic ring Ø In many cases, the amine may be protonated when it interacts with the target, meaning it’s ionized and cannot act as a HBA. However, it can still act as a HBD or could interact with a carboxylate in the binding site There are lots of new terms in here that are very important, so let’s take some time to remind/inform ourselves of what they mean! Structure Activity Relationships (SARs) The binding role of common functional groups Amines Ø Amines are very important FGs in drug molecules Morphine Strychnine Nicotine Coniine Structure Activity Relationships (SARs) The binding role of common functional groups Amines Ø Can act as HBDs and HBAs Structure Activity Relationships (SARs) The binding role of common functional groups Amines Ø Amines can be primary, secondary or tertiary and each can form different number of H-bonding interactions as the HBD Structure Activity Relationships (SARs) The binding role of common functional groups Amines Ø Aromatic and heteroaromatic amines can only act as HBDs, as the lone pair interacts with the (hetero)aromatic ring  Structure Activity Relationships (SARs) The binding role of common functional groups Amines Testing the binding role of amines. Ø To test whether ionic or hydrogen bonding interactions are taking place, swap to an amide analogue Ø Prevents nitrogen acting as a HBA, due to resonance Ø Let’s draw these resonance structures Ø Relatively easy to form primary and secondary amides from primary/secondary amines respectively Ø Examine the HBD and HBA capabilities of primary, secondary and tertiary amides Question: there is a positive charge on the nitrogen in one of the resonance structures. Why will this not act as a HBA? Structure Activity Relationships (SARs) The binding role of common functional groups Amides Testing the binding role of amides. Ø Amides are very common in drugs (e.g. peptides) and secondary amides are the most common Ø What information would the following drug analogues provide (i.e. if you swap the secondary amide to each of the following, what will it tell you and why? Why might the alkene analogue be useful? Secondary amide N-methylated amide Secondary amine H Me H N R R N R N R R R O O Alkene N-methylated Ketone Carboxylic acid tertiary amine HO R R Me R R N R R O R O Structure Activity Relationships (SARs) The binding role of common functional groups Amides Testing the binding role of amides. Ø β-lactams are cyclic amides Ø The motif is found in the penicillin drugs Ø The ring strain is a key feature of the biological activity of these drugs (acts as an acylating agent and forms covalent bond with bacterial enzyme by acylating serine residue) β-lactam N O Structure Activity Relationships (SARs) The binding role of common functional groups Quaternary ammonium salts Ø Quaternary ammonium salts are ionized (always have a + charge on N) Ø Can interact with carboxylate groups in target or induced dipole (π-cation) interaction with aromatic ring in the binding site Ø Could convert to tertiary amine to check importance of the group – but the amine could also become protonated Ø Could change to an amide (amine to amide) would prevent this CH3 O H 3C N H 3C O CH3 Acetylcholine Structure Activity Relationships (SARs) The binding role of common functional groups Carboxylic acids Ø Can act as HBA and HBD Ø May exist as carboxylate ion, where there is the possibility of ionic interactions or very strong H-bond acceptor Ø Carboxylate is also a good ligand for metal ion cofactors present in several enzymes Structure Activity Relationships (SARs) The binding role of common functional groups Carboxylic acids Ø Synthesize ester, primary amides, primary alcohols and ketones could be tested as analogues Ø None can ionize, so loss of activity could mean ionic interaction is important Structure Activity Relationships (SARs) The binding role of common functional groups Esters Ø Esters can only act as HBAs (not donors) Ø The carbonyl oxygen has greater electron density and is less hindered than the alkoxy oxygen, so will typically be a better HBA Ø The relevance of the carbonyl group could be tested by making the equivalent ether analogue Ø Esters can be susceptible to hydrolysis by enzymes and reduce the stability of the drug, but many drugs do contain them Ø Because esters are prone to metabolic hydrolysis, they are often used in prodrugs (we will look at prodrugs in some detail later) O OH O OH hydrolysed in vivo O O OH Aspirin salicilic acid Note: this is the proposed mechanism. Aspirin thought to be hydrolysed in vivo to generate active drug Structure Activity Relationships (SARs) We have not covered every group and possible analogue, but this should give you a good flavor of SAR Testing Procedures In vitro: outside the cell In vivo: inside the cell Ø Initial tests to investigate structure-activity relationships should be carried out in vitro ? Can you think why? ? What important information can in vivo tests reveal?  SAR in Drug Optimisation Ø SAR is also used in drug optimization studies, where the aim is to find analogues with better activity and selectivity Ø Once the important binding group have been identified, the next stage involves identification of a pharmacophore Ø A pharmacophore is a molecular skeleton containing the essential binding groups in their relative positions in space with respect to each other A molecular framework that bears (phores) the essential features responsible for a drug’s (pharmakon) biological activity IUPAC: an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response IUPAC – International Union of Pure and Applied Chemistry https://www.cureffi.org/2015/06/19/the-curious-antiprion-activity-of-antimalarial-quinolines/ Pharmacophores A pharmacophore is a molecular skeleton containing the essential binding groups in their relative positions in space with respect to each other It is very common that the same structural motif will make up the pharmacophore. However, pharmacophores do not have to be structurally identical, because different FGs can have the same effect i.e. same interactions HBD HBD HBD N N F O O NH2 NH N N F N F F N N N O N S F O OH HN F OH All three have a correctly positioned HBA All three have a ‘F’ interacting with the target So what are all these other functional groups doing on the drugs? Why not just use the pharmacophore? Drug Optimisation Strategies Ø Identifying 3D pharmacophores is straightforward for rigid structures, such as hypothetical glipine Ø It is not as straightforward with more flexible structures, because the molecule can adopt many conformations. However, only one conformation is recognized by the binding site Ø This conformation is known as the active conformation Ø One problem with pharmacophores is that they only consider functional groups as important binding groups - van der Waals interactions in other parts of the molecule are ignored – these can be crucial for binding - the size on the molecule is not taken into account Drug Optimisation Strategies Ø Once a lead compound and pharmacophore has been identified, why bother making analogues? Ø Lead compounds rarely have optimal properties. They may suffer from: v Low activity v Poor solubility v Toxicity v Instability v Poor selectivity Ø There are several strategies used to optimise a drug (and we will look at some!) Drug Optimisation Strategies Variation of substituents Drug Optimisation Strategies Extension of the Structure Ø This strategy involves the addition of another functional group or substituent to the lead compound to look for additional binding interactions Ø Often used to look for extra hydrophobic binding regions Drug Optimisation Strategies Extension of the Structure An example Morphine Drug Optimisation Strategies Chain Extension Ring Expansion/Contraction Drug Optimisation Strategies Ring Variations Ø Replacing an existing heteroaromatic ring with alternative rings is a common approach Ø For example, several non-steroidal anti-inflammatory agents (NSAIDs) have a similar central ring with a 1,2-biaryl substitution Ø Various pharma companies have varied the central ring* *note: this is often to get around patent restrictions (known as ‘me too drugs’ but not always, and some have improved activity Drug Optimisation Strategies Simplification Ø Simplification is a strategy often used on lead compounds discovered from natural sources (natural products) Ø Involves systematically removing function groups and checking to see if the activity is affected Ø It may be particularly useful to remove chirality centers from a drug (reasons discussed in later lecture) Drug Optimisation Strategies Simplification Example Ø Morphine, levorphanol and metazocine are all analgesics Ø Analgesic pharmacophore is retained despite simplification Analgesic Analgesic Analgesic pharmacophore pharmacophore pharmacophore retained retained HO HO HO O N CH3 N CH3 Me N CH3 H H H H H H Me HO Morphine Levorphanol Metazocine Excess functional groups Excess ring Drug Optimisation Strategies Rigidification of Structure Drug Optimisation Strategies Rigidification of Structure Ø Endogenous lead compounds are often simple and flexible Ø Fit several targets due to different active conformations Ø Results in side effects Single bond rotation + + Flexible chain Different conformations Strategy Ø Rigidify molecule to limit conformations - conformational restraint Ø Increases activity - more chance of desired active conformation being present Ø Increases selectivity - less chance of undesired active conformations Disadvantage Ø Molecule is more complex and may be more difficult to synthesise Drug Optimisation Strategies H NH2Me Rigidification of Structure H O O NH2Me Bond H rotation H I II -O C 2 Ø May result in selectivity issue H H NH2Me O -O C O H O O H 2 NH2Me H H RECEPTOR 1 RECEPTOR 2 Drug Optimisation Strategies Rigidification of Structure Approach – introduce rings Ø Bonds within ring systems are locked and cannot rotate freely Ø Test rigid structures to see which ones have retained active conformation Example Example Rotatable bonds Fixed bonds OH OH Rigidification OH O Rotatable bonds HN HN CH3 CH3 Flexible messenger Rigid messenger Drug Optimisation Strategies Rigidification of Structure Approach – introduce rigid functional groups 'locked' bonds O C NH Rotatable Example bond Z-Isomer E-Isomer Less active Combretastatin A-4 Combretastatin More active Drug Optimisation Strategies We have not discussed all the optimization strategies in drug design – but a very good taste of them! Pharmacokinetics Some Important Definitions Ø It is vital to understand what effect the drug will have on the organism (animal (including human), bacterial… Ø The study of how a drug effects its target is known as pharmacodynamics Ø It is equally as important to know what effect an organism will have on the drug! Ø This study is known as pharmacokinetics Ø So, pharmacokinetics is the study of how an organism affects a drug, whereas pharmacodynamics is the study of how the drug affects the organism Pharmacokinetics - Definition Ø Key concepts Absorption Distribution Metabolism Elimination v What the body does with a drug Ø How well is the drug absorbed? Ø Does it get distributed to the right places? Ø How does the body break down the drug? Ø How fast does the body break down the drug? Ø How is the drug eliminated from the body? Getting to the Target Routes of administration Ø Oral Ø Inhaled Ø Intravenous or intra-muscular injection Ø Intranasal or sublingual (under the tongue) Ø Suppositories Barriers that oral drugs must overcome Ø Drug must dissolve (stomach acid) Ø Absorption by intestine (cross membranes) Ø Metabolism by liver, clearance by kidney Ø Distribution by blood to site of action Ø Diffusion to biological target Pharmacokinetic parameters The concentration of a drug in the body is always changing Ø Plasma half-life t1/2 (hr) The time taken for the drug plasma concentration to fall to half its original value Ø Clearance rate (CI) (mL/min/kg) The rate at which a unit volume of blood is cleared of the drug (usually Clearance = Elimination) Ø Oral bioavailability (F) The fraction of the drug that enters systemic circulation after oral administration F = 50% means half the dose has been lost before getting into the blood stream due to low absorption and/or by ‘first pass’ metabolism in the liver Ø Volume of distribution Vd (L/kg) A theoretical volume occupied by the total drug dose if the drug was evenly distributed Absorption & Distribution Absorption Ø How the drug enters the bloodstream Ø It’s important to balance aqueous solubility with membrane solubility Ø Hence log P in range 1-3 Distribution Ø Drug carried around body in the bloodstream and diffuses everywhere Ø Drug loosely bound to plasma proteins or ‘free’ Ø Blood-brain barrier may limit entry to the brain Oral drugs that follow Lipinski’s rules can often result in good absorption, but following these rules may result in poor metabolic stability! Metabolism Ø The objective of metabolism is to make a drug more polar so that it can be removed from the body (kidneys) Phase I – oxidation, reduction, hydrolysis Phase II – conjugation Ø Rapid metabolism means that little drug reaches the blood and that the drug has a short plasma t1/2 Ø Metabolism occurs mostly in the liver (also a little in GI tract, blood, kidney) Ø Phase I metabolism is carried out by various enzymes - cytochrome P450s (CYPs), monoamine oxidase, flavin monooxygenase, xanthine oxidase, esterases/peptidases (hydrolysis) Phase II metabolism typically catalysed by transferase enzymes– glucuronidation and sulphation; glutathione Phase I Metabolism Oxidative metabolism Reactions mediated by CYPs At carbon where a radical can be stabilised CH3 H 3C CH3 = radical H 3C O CH3 N H 3C CH2 Aromatic & heteromatic rings, alkenes, sulphur O aromatic oxidation O epoxidation O HO aromatic ether alkene epoxide O S S S There are a number of mammalian P450 isoforms, sulfide O sulfoxide O sulfone which carry out various crucial roles in human metabolism. The chart above shows these isoforms that are involved Electron rich groups are most prone to oxidation in drug metabolism. It is essential for pharmaceutical O companies to understand what happens to drugs in the body N O N N N as a result of the action of CYPs. They must establish if the metabolites are toxic or possibly more active. pyridine N-oxide amine N-oxide Potential drug-drug interaction involving the metabolites must also be evaluated. Phase I Metabolism Metabolism by hydrolysis Ø Esterases and peptidases can potentially hydrolyse any ester or amide in vivo hydrolysis CO2Et Esterase CO2H N (in plasma) N N N Etomidate Ø Etomidate is a short-acting intravenous anesthetic, which is inactivated in the blood plasma by the actions of esterases. The enzyme hydrolyses the ester to the corresponding carboxylic acid test – draw out the two molecules and the functional groups in full – it’s vital to recognize functional groups Phase II Metabolism Metabolism by conjugation Ø Glucuronidation/sulphation occur typically at phenol, alcohol and carboxylic acid groups (examples on next slide) Ø The OH group may have been already present in the drug, or added during phase I metabolism Ø The process is enzyme mediated (transferases) Ø The products of conjugation are typically higher in MW and less reactive than the parent compounds Ø This is in contrast with Phase I metabolism, where products are often more reactive UDP coenzyme (cofactor) Excretion We will not discuss Excretion Physiochemical Properties of a Drug Ø Physiochemical properties significantly effect the performance of the drug in vivo Ø Many drugs are active in vitro but fail to work in patients Ø Medicinal chemists can control physiochemical properties by design What makes a successful drug? Ø Good activity and selectivity for the biological target (we have discussed this quite a bit) Ø But this is not enough…. Ø The drug must reach the site of action and remain there for long enough to be effective A. Y. Abuhelwa et al. Eur. J. Pharma. Biopharma. 2017, 112, 234. Physiological pH Blood, inter- & intra-cellular space pH 7.4 pH 1-1.5 pH 5.5 pH 8 Ø The pH in the body varies widely Ø This has a major effect on the ionization state of drugs Ionisation and pKa Ø Drug ionization effects: Potency, solubility, pharmacokinetics and metabolism Ø pKa refers to the dissociation of H+ Ø It is the acid dissociation constant and is a measure of the strength of the acid Ø It can be confusing when talking about bases!!! Ø For now, we will keep our discussions of pKa relatively simple – but let’s just look at amines and carboxylic acids in a bit of detail Ionisation and pKa Remember: high pH = basic O O low pH = acidic Ka OH O + H+ Acid Acid Conjugate base pKa = 4.2 H Ka1 N CH3 + H+ Ka2 N CH3 N CH3 + H+ Base H H Conjugate acid Base Not relevent in water pKa = 9.3 Ø The pKa is the pH at which 50% of the compound will exist as the ion (protonated for a base/deprotonated for an acid) Ø At pH 4.2, 50% of benzoic acid will be deprotonated. As the pH increases (even a small bit!), more and more of the molecule exists as the ion Ø At pH 9.3, 50% of benzylamine will be protonated (and the other 50% as the unprotonated form of the molecule). As the pH decreases, more of the molecule will exist as the ion Ionisation and pKa So what should you understand at this stage….. Ø Carboxylic acids will be deprotonated at physiological pH and many amines will be protonated! Ø pKa can affect the ionization state of both the drug and the drug targets (amino acids) O NH2 Drug Drug OH Mini problem Ø Draw the drug containing the carboxylic acid at pH 3.4 and pH 7.4 Ø Draw the drug containing the amine at pH 7.4 Lipophilicity Ø Measuring how a drug partitions between plasma and cell membranes is very difficult and expensive Ø Lipophilicity is typically measured as the proportion of drug portioned between water and octanol Ø It can also be measured by reverse-phase chromatography Ø Log P = log ([drug]oct/[drug]water) Ø To account for ionized drugs, use D (Distribution coefficient) and log D (at defined pH) [drugunionised]oct LogD = log [drugionised]water + [drugunionised]water Lipinski’s ‘Rule of 5’ Chris Lipinski (Pfizer) analysed data for many oral drugs that had progressed to clinical trials and concluded that: A drug is likely to have poor solubility and absorption if Ø Molecular weight > 500 Ø logP > 5 Ø No. of H bond donors > 5 (just counting OH, NH and SH) Ø No. of H bond acceptors > 10 (just N and O) So Lipinski’s Rule means a drug should have: A molecular weight less than 500 No more than 5 HBD groups No more than 10 HBA groups A log P value less than +5 Lipinski et al. Adv. Drug Delivery Rev. 1997, 23, 3 Lipinski’s ‘Rule of 5’ Molecular weight (molar mass) Example: Calculating molecular weight O OH piroxicam logP = 3.0 N N H MW = 331.35 N H 3C S O O Lipinski’s ‘Rule of 5’ Why does it (often) work? Ø Drug must be able to move from water through biological membranes Ø Loss of water of solvation (enthalpy loss/entropy gain) Ø Must not have too many H bond acceptors/donors Ø At logP > 5: aqueous solubility will be very low – hence poor absorption Ø MW rule: to comply with other rules, need to Aqueous Hydrophobic balance number of polar and non-polar atoms H H H O O Ø This is increasingly difficult as MW approaches O H H H 500 H H O OH O O OH N N H N N O H H C N S H N 3 H O O O H 3C S H H H O O O H H O H Lipinski’s ‘Rule of 5’ Atenolol (beta blocker - blood pressure) Torcetrapib (cardiovascular disease) OH O H O N CF3 NH2 O N F3C O logP = 0.23 logP = 7.0 MW = N Et MW = HBD = HBD = HBA = O O HBA = C = 12.011; N = 14.007; O = 15.999; F = 18.998; S = 32.06 H = 1.008; C = 12.011; N = 14.007; O = 15.999; F = 18.998; S = 32.06 Drug Properties Lipinski’s ‘Rule of 5’ Journal of Medicinal Chemistry MW of compounds approved before and after this time (Figure 5), it becomes apparent that the higher MW Ø The ‘rule’ is useful for selecting oral drug candidates compounds entering clinical trials did not fail as they proceeded through clinical trials as originally hypothesized. Ø It is not always correct Since 1997, pharmaceutical industry productivity, as measured by number of FDA approved oral drugs, has increased while the number of MW < 500 drugs has remained relatively Ø Compounds that follow the rule can be unsuitable and compounds at disobey constant theslightly or declined rule can be6).excellent (Figure drugs in Thus, the increase Figure 6. Number of FDA approved oral drugs grouped by time period. Oral drug approvals with MW less than 500 are colored blue, and those above 500 are colored red. J. Med. Chem. 2019, 62, 1701−1714 Drug Properties Arguments against the rule’ Ø The rule may be too generous Ø Suggestions: Ø MW < 300 Ø LogP < 3 Ø HBA < or = 3 Ø HBA < or = 3 Ø Also, the idea that molecules should contain < 10 rotatable bonds why do you think this is important? Let us now look at how all of these properties are important for drug pharmacokinetics Tackling Drug Solubility Make the Salt! Ø Drugs are frequently converted to salts where possible Salts are typically solids – it’s much easier to weigh out and handle than liquids/oils Increased chemical stability stability/shelf-life Increased kinetic solubility (dissolution rate) Ideally non-hygroscopic, non-hydrated or solvated Ibuprofen is the lysine salt. - think about the origin of these charges O NH3 O O H 3N O ibuprofen lysine Prodrugs Ø A prodrug is a drug that is administered in an inactive form and is converted to the active form of the molecule in vivo Ø Prodrugs can be used to enhance the lipophilicity of a drug REVIEWS a should be considered with respect t dose and the duration of therapy. Enzymatic Drug and/or chemical Parent and prodrug: the absorpt transformation metabolism, excretion (ADME) and properties need to be comprehensi Degradation by-products: these ca Drug Promoiety Drug Promoiety Drug + Promoiety and physical stability and lead to new degradation products. Barrier Some of the most common function Ethers amenable to prodrug design include ca b Carbonates OR amine, phosphate/phosphonate and O R1 O Prodrugs typically produced via the mo O OR –SH O O R2 groups include esters, carbonates, car Prodrugs Ø Esters are the most common prodrugs used Ø Ester prodrugs are often used to enhance the lipophilicity making it easier for the drug to pass through membranes Ø This is achieved by masking charged functionality – carboxylate ion Ø Once in the body, the ester is cleaved to give the carboxylate – the active form of the drug O O esterase + H 2O HOR1 R OR1 R OH O O esterase + HOEt O H 2O OH Note: I have drawn the carboxylate acid (protonated) but in vivo, these FGs would typically exist as the carboxylate ion Prodrugs O O HO O esterases N N N N H H COOH O COOH O Enalapril Enalaprilat (angiotensin-converting enzyme inhibitor) O O O O O esterases OH O N O N H H NH2 NH2 Oseltamivir Oseltamivir (anti-influenza) Prodrugs Problem N N H 2N N N Esterases penciclovir O O O O Famciclovir (antiviral) Problem: what product would you expect - i.e. what is the structure of penciclovir The Importance of Chirality in Drug Design and Discovery Ø What is a chirality (chiral) center? - the term ‘chiral center’ has been replaced with ‘chirality center’ Ø Let’s focus on carbon! (other atoms can also be chirality centers) Ø A molecule is chiral if it cannot be superimposed on its mirror image Ø For a carbon atom to be a chirality center, it must have four different groups bonded to it Ø Models are useful to help visualize this concept The Importance of Chirality in Drug Design and Discovery Ø A molecule containing a single chirality center can exist as two enantiomers Ø A molecule that contains more than one (often many) chirality centers can exist as a potential number of epimers Ø Drug receptors are typically proteins, made up of chiral amino acid residues – a chiral environment Ø Chemical properties of enantiomers are mostly the same Ø It’s important to mention that compounds with more than one chirality center are more complex, and can exist as different stereoisomers with distinct chemical properties – we will not discuss this in detail Ø Melting points; boiling points; tlc – must use chiral stationary phase to separate enantiomers by liquid chromatography Ø However, the chiral environment of drug targets of metabolic enzymes ‘see’ the enantiomers differently Ø This can have significant consequences for chiral drug molecules The Importance of Chirality in Drug Design and Discovery O O H H (S)-carvone (R)-carvone oil @ 25 deg C oil @ 25 deg C bp: 230-231 deg C bp: 230-231 deg C d: 0.965 g/mL d: 0.965 g/mL Thalidomide Smells like mint Smells spicy Ø While enantiomers can have mostly the same chemical properties, they can have vastly different biological activity Ø Vital to have access to the individual enantiomers and evaluate both in vivo Ø This can complicate drug design and biological evaluation The Importance of Chirality in Drug Design and Discovery Ø Drug molecules do not have to be single enantiomers– but both enantiomers must be tested to ensure they are safe Questions: Why do we need to consider/test both enantiomers of a drug? Why can this be complicated? Lecture Summary Brief history of the pharmaceutical industry (not examined Timeframe from discovery to market We considered some drug properties Structure of cells Intermolecular interactions – H-bonding; electrostatic H-bonding in Nature Intermolecular interactions continued – van der Waals Structure of amino acids (importance of their side chain) Introduction to drug targets (enzymes) Primary, secondary and tertiary structure of proteins Introduction to how enzymes work Catalytic mechanism of a protease (the mechanism will not be examined. I gave this example to give you an appreciation of the complexity and elegance of enzymes) HIV life cycle to highlight potential drug targets. (life cycle itself not examined. This was to get you thinking about various drug targets) Ion channels; GPCRs; nuclear receptors Lecture Summary Structure activity relationships (SAR) Binding role of common functional groups Introduction to resonance structures (we looked at this for amides, as an example) Importance of testing in vitro and in vivo SAR: Have a think about all these functional groups discussed and what each functional group change/swap might tell you! Use of SAR in drug optimization Pharmacophore – what is it? Can you recognize one from a panel of similar drugs; Why is it useful to establish the pharmacophore. Terminology: active conformation; lead compound Why necessary to optimize lead compound Drug optimization strategies: variation; extension of structure; chain extension; ring expansion/contraction; ring variation; simplification; rigidification. These are important concepts for any medicinal chemist so please be familiar with them! Drug optimization in-class problems Introduction to pharmacokinetics ADME Pharmacokinetic parameters: half-life; bioavailability; clearance rate Lecture Summary Phase I (P450s/esterases) and Phase II metabolism (Glucuronidation) A brief look at physiochemical properties of drugs pH variation between various areas of the body Drug ionisation; pKa (carboxylic acids and amines) Lipophilicity and how measured (LogP; LogD) Lipinski’s Rule of 5 Reason for making drug salt Prodrugs (a brief introduction) Importance of chirality in drug discovery and optimisation Closing thoughts…. Ø My role is to deliver relevant material that will enhance your knowledge and understanding of the subject Ø You are not here to learn how to pass exams (imagine if that’s the attitude that trainee doctors took!!) Ø I like the term ‘chemically literate’ - and this is what you should strive to be Ø Be a problem solver – understand – learn as little as possible! Ø ”a collection of atoms that can contemplate atoms” Prof Brian Cox – Professor of Particle Physics at the University of Manchester