PHM2006 Medicinal Chemistry for Pharmaceutical Professionals PDF

⚗️ PHM2006 - medicinal chemistry for pharmaceutical professionals Tags CUHK Term 5 Major Required PHAM Lecture Unit 1: Introduction to Drug Development and Discovery Introduction to Drug Development...

⚗️ PHM2006 - medicinal chemistry for pharmaceutical professionals Tags CUHK Term 5 Major Required PHAM Lecture Unit 1: Introduction to Drug Development and Discovery Introduction to Drug Development Drugs: Any chemical molecule that affects living tissues. Drugs can be divided into two types: Those that can be synthesized by your body (e.g. hormone replacement therapy) Those that can’t be synthesized by your body (xenobiotics) Xenobiotics are the majority of drugs. Poisons are drugs delivered on a lethal dose. Therapeutic index: A ratio that expresses the relationship between the dose expected to elicit some adverse effect and the dose needed to elicit therapeutic effects. (Median of the lethal dose divided by the median of the effective dose.) T herapeuticIndex = LD50/ED50 Poisons may be turned to effective drugs under supervision. Example: Legalized use of cannabis for medical purposes; arsenic that can cure cancer (deadly to cells); alcohol D-tubocurarine (used by Native Americans to poison their arrows, but is actually an receptor antagonist for nicotinic acetylcholine receptor (nAChr)) is used as a muscle relaxant in surgical operations. Drugs do not cure your disease, but they focus on making the patient feel better and allow their immune system to fight against the disease. Receptor agonist vs antagonist: PHM2006 - medicinal chemistry for pharmaceutical professionals 1  Agonists bind to a receptor so that the receptor can proceed with their natural function. Antagonists block receptors, stopping a certain natural process taking action. Receptor antagonists can be classified as competitive inhibitors. Example of an antagonist in the lecture —> refer to tubocurarine Medicinal chemistry classifies drugs based on their target molecules. Pharmaceutical scientists study the type of drugs based on a certain nomenclature that identifies their chemical structure and their lethal dose/therapeutic index. Brand names must have their first letters capitalized. Generic names must not be capitalized at all. Brand names don’t tell much about the drug. Therefore, generic names must be used to discuss the functionalities of the drug. Example: The generic names ‘saquinavir,’ ‘ritonavir,’ ‘indinavir’ show that they are antiviral drugs (-avir suffix). Reference: https://accesspharmacy.mhmedical.com/content.aspx? bookid=1549&sectionid=93411751 Three most important names of a drug: Chemical name (IUPAC), generic name, and trade name. Chemical names are just for regulations and are difficult to use among pharmaceutical experts —> they’re so long :( Generic names are for those who advertise the drugs. Brand names depend on the company who sells the drugs. Biologics include extraction from natural biological sources for repurposing into drugs. Example: Hormones from pregnant people that can be extracted before premature abortion is conducted. Biopharmaceuticals involves modern biotechnological and computational design techniques in order to modify existing sources to be used as pharmaceuticals. Observation of natural products is the basis of early drug development. Medicinal chemistry is involved with the optimization of chemical products. For instance, an existing product can have its affinity to its target modified. PHM2006 - medicinal chemistry for pharmaceutical professionals 2  Adding a functional group can be one way to optimize a chemical product. Many drugs used today is discovered from natural resources. Example: Cocaine is derived from coca leaves, which are found to prevent the ion reuptake in neurotransmitters. Drug discovery relates to finding a suitable chemical candidate to be profiled as a drug. Bioassays are created to screen numerous chemicals’ activity against a particular, predetermined target. Which one is the most potent? Drug design can also be done on targets that are obtained from tissues or genes extracted from patients. We compare the result to the healthy population to receive the result/effect of the drug on the target molecule. Molecular docking: A type of computational analysis that determines a certain part in a drug molecule and a target protein that can be bound. A database of these active sites is kept for further research. Optimization of drugs usually involve the increase of selectivity and effectiveness of that drug. Many widely used drugs are not that selective —> leading to side effects Example: An asthma inhaler might have side effects as the drug doesn’t simply bind to the necessary histamine receptors. Structure-Activity Relationship: Which functional group in a molecule that can bind in the target’s pocket. Focuses on improving the drug-receptor interaction. QSAR attempts to quantify the physical properties of a drug and their effect on its biological activity. (e.g. hydrophobicity of a drug affects how it interacts with its target) Today’s pharmaceutical research is heavily focused in optimizing existing products as well as their production (e.g. enhancement from X-rays and filtration has increased the production of penicillin throughout the years). Drug Discovery: Finding a Lead PHM2006 - medicinal chemistry for pharmaceutical professionals 3  Drug discovery is a difficult phase in pharmaceutical research — its success rate is estimated to be 50%. Example of drug discovery: Parkinson’s disease Parkinson’s is caused by insufficient dopamine. Solution: Create a drug that induces dopamine production. Problem: Dopamine is not just produced in the brain, but our entire nervous system. Question: So, how do we only target the problem in the brain? What is exactly causing this malfunction and how do we directly address/target this problem? The focus of drug discovery is to find which target we can address with a drug to resolve a problem. NMR bioassays will use a comparative analysis between the regular signals and the signals after the addition of protein. A lead will have different signals because it binds to a large biomolecule (protein). For example, the addition of albumin could’ve created arginine nucleic acids instead of only tryptophan —> creates a difference that is caused by albumin binding. NMR not only requires a significant quantity of the target, but is also very expensive. The increase of SPR’s signal is proportional to the concentration of the candidates because of the binding of the candidates and the ligands. SPA’s radioactive energy makes it easy to use and detect. ITC measures if two molecules are bound together, they will generate less heat together compared to when they’re separated. The temperature of the solution in the ITC is kept constant and higher than the room temperature. Because of this constant state, the bound molecules are allowed to generate less heat. Why would they generate less heat? Because this binding state allows them to stabilize —> doesn’t generate the same amount of energy anymore. The sample cell in ITC provides the chemicals for the ligand solution. The ligand solution injects their ligands to the molecules in the sample cell. PHM2006 - medicinal chemistry for pharmaceutical professionals 4  Stereospecific reaction: The final product depends on the conformation of the reactant. (Because one reactant has a specific reaction.) Stereoselectivity: A compound has several candidates to react with, but sometimes holds a degree of preference to a certain candidate. Example: Two enantiomers have a similar product when reacted with a molecule. Target specificity and selectivity: The drug should only target a certain receptor/enzyme type within a certain part of the body. Agonist vs Antagonist A pitfall of agonists is that our biological molecules (e.g. proteins) have different ways to circumvent our agonists’ actions, rendering them useless. We have to design a chemical effective enough to prevent this pitfall. Sometimes, we even need to adjust our drug target to effectively solve our problem. People often aim to get rid of side effects of a drug, as they can be damaging to the body, but side effects can be enhanced too. Natural products are really complicated to screen. (e.g. Is this even a correct isomer?) Basic concept of fragment-based lead discovery: Finding an appropriate molecule that can fit into the epitope of the protein. NMR is important in this study because it can detect which protein pocket (epitope) is the small molecule inhabiting in. (In other words, it’s important for researchers to optimize which molecules are appropriate for different epitopes.) The location of the epitopes are also important (also detected by NMR!) because if the locations are too far apart these molecules cannot do covalent bonding with each other, which diminishes their activity. Example of a difficult drug to administer: Keytruda, which is a large molecule. The dosage system is long-range, once in every 3 or 6 weeks. Analogues are synthesized to find out which analogue has the best affinity to the target, and which functional group is the most important to bind to the target. Hydrogen bonding only qualifies as one if both reactants have hydrogen atoms to bond with! PHM2006 - medicinal chemistry for pharmaceutical professionals 5  Covalent bond is the strongest force, followed by ionic bonding, H-bonding, dipole- dipole, and van der Waals. The relative strengths of these interactions are affected by environment, hence they are subject to change. However, the order of their strengths will never change. Unit 2: Drug Design Drug Design and Optimization Drugs must be designed with multiple interactions cooperating with each other to maximize its use. Hydrophobic interaction is only effective in water. How hydrophobic interaction works: Water molecules will be inclined to interact to any molecule to form hydrogen bonding. However, the hydrophobic molecule will only allow the water molecules to orient themselves to the total surface area of the molecules, forming a structured layer. This deforms the water’s hydrogen bonding. The hydrophobic molecules would structure together to minimize free energy of the system (reduces the hydrogen bonding’s disruption and increases entropy by releasing structured water molecules around them). This also reduces the surface area exposed to water. Unlike alcohol, methyl ether cannot bond with an oxygen receptor because of the steric shield the methyl group gives out. Aromatic rings allow for interaction between the flat hydrophobic binding region, something that nonaromatic rings can’t do. Aromatic rings are planar. The flat surfaces allow for maximized contact area for van der Waals interactions. van der Waals is already weak, so they need more contact area to bind well. Hydrophobic effect also contributes to binding. The major reason why flat hydrophobic regions bind well with aromatic rings is because hydrophobic regions contain plenty of dispersion forces (that’s what bind hydrophobic molecules together to ‘repel’ water). Combined with PHM2006 - medicinal chemistry for pharmaceutical professionals 6  the large surface area between a planar aromatic ring and a flat hydrophobic region, cumulated dispersion forces can bind these two molecules, making them compatible. Nonaromatic rings are not flat and have different conformations. They don’t fit well with flat hydrophobic regions for this cause. They also have flexible conformations, which can be unfavorable for binding. They can still bind with pockets that match their shape. π–π interaction occurs between aromatic rings and flat hydrophobic regions. Rotating an alkene (changing its conformational isomer) might give out a different binding outcome. Alkene is still a rigid molecule and cannot be rotated that simply. Generally, protonated amines have stronger hydrogen bonding. Although amides can be used to prevent amines’ nitrogen forming a hydrogen bond, amides can still be used in hydrogen bonding through its hydrogen or oxygen. Amide-analogue alkene, like regular alkenes, cannot be rotated. In some cases, rigidity can be beneficial if it locks the molecule in the exact right conformation for binding. It's about matching the rigidity to the specific receptor's requirements. Deprotonation of carboxylic acid prevents it becoming a hydrogen bond donor. Esters’ hydrolysis is a good example of how different in vitro and in vivo testing may result. Alkyl halide’s affinity to a nucleophilic group is very strong. But alkyl and aryl fluoride cannot react with amine groups. Aryl halides typically do not react directly with alkyl amines under standard conditions, unlike alkyl halides. This difference in reactivity is due to several key factors: 1. Aromatic stability: The carbon-halogen bond in aryl halides is part of an aromatic system. This aromatic character makes the bond more stable than in alkyl halides. PHM2006 - medicinal chemistry for pharmaceutical professionals 7  This is the reason why the required activation energy would be massive. 2. Resonance effects: The halogen's lone pairs can delocalize into the aromatic ring. This strengthens the carbon-halogen bond, reducing its reactivity. 3. Poor leaving group in aromatic systems: Halides are poor leaving groups when attached to sp2 carbons in aromatic rings. This is unlike alkyl halides, where halides leave more readily from sp3 carbons. 4. Lack of backside attack: SN2 reactions, common for alkyl halides, require backside attack. The planar aromatic ring prevents this approach. 5. Unfavorable transition state: Nucleophilic aromatic substitution would involve a high-energy transition state. Requires a lot of activation energy! This state would temporarily disrupt the ring's aromaticity, which is energetically costly. However, aryl halides can react with amines under specific conditions: With activated aryl halides (e.g., those with electron-withdrawing groups). Under harsh conditions (high temperature/pressure). Bypasses the required activation energy. Cannot be replicated within the human body. Using metal catalysts (e.g., palladium-catalyzed coupling reactions). Via SNAr mechanism for certain activated aryl halides. These special cases often require specific structural features or reaction conditions that overcome the inherent unreactivity of typical aryl halides towards nucleophilic substitution by alkyl amines. Reminder: Acidity is determined by how easy H+ dissociates from the molecule. PHM2006 - medicinal chemistry for pharmaceutical professionals 8  So, iodine has the biggest radius —> negative charge is distributed in a larger scale —> H+ easily dissociates. HF is strong electronegatively —> difficult to dissociate The selectivity of the alkylation cannot be improved like other drugs because it often involves the formation of covalent bonds between a drug and its target. This is different from many drugs that work through non-covalent interactions. Alkylating agents can potentially react with many nucleophilic sites in biological systems, not just the intended target (multi-point interactions). Tautomerization is important to understand because different resonant structures will give into different pairings —> different results Pharmacophore —> Identification of functional groups that bind to the proteins Alkyl halides are easily substituted. Electron density will increase in an ortho-position. Extending or contracting an aromatic ring changes the relative position of the molecules —> Can be a defining factor in a drug’s success in binding. Suppression of chemical rotation (Making the molecule rigid) can reduce a molecule’s entropy and enhance its binding. We must think of pharmacokinetics when choosing a drug candidate. A drug’s property should be optimized between hydrophobicity and hydrophilicity so that it can pass the cell wall. Partition coefficient is used to determine this property of the drug. An aqueous solution and an organic solvent is brought in the experiment, and they will not mix (will be partitioned) How does hydrophilicity equate to polarity in this context? Water is very polar. (The electronegativity of oxygen contrasts against hydrogen.) This allows water to interact with other polar molecules through dipole-dipole interactions. PHM2006 - medicinal chemistry for pharmaceutical professionals 9  This compound is too hydrophilic and it’s difficult for it to interact with the hydrophobic parts of the cell. Therefore, a drug still needs hydrophobic groups in order to interact effectively with the body. Increase of electronic density may increase a drug’s resistance to degradation. Prodrug can ‘sneak’ in a drug that would otherwise be unacceptable by the body. The idea of prodrugs disguising themselves to ease crossing through cellular membranes comes from the concept that drugs will be metabolized inside the body, and prodrugs will hopefully be metabolized into an active form through natural reactions in the body. The reason why Levodopa is used to treat dopamine insufficiency is its capability as a ‘Trojan horse’ to deliver itself as a dopamine analogue while having a -CH(NH2) (COOH) group, which will cause the blood-brain barrier (BBB) to misinterpret it as an amino acid, allowing it to pass through the brain. By having glutathione slowly convert the prodrug azathioprine into its active form, 6-Mercaptopurine, we can prolong its activity by maintaining the drug’s concentration in our body. Azathioprine is effective in prolonging its interaction with glutathione by creating an electron deficit area in the compound while having -NO2 (an electron-withdrawing group) near the electron deficit area. Valium prolongs its activity in the body by having a hydrophobic methyl group instead of a hydrogen atom. Aspirin masks salicylic acid’s toxic phenolic group by turning it into an ester. If the ester is slowly hydrolyzed by the body into a phenol, it will reduce the risk of side effects. Carbidopa is used as a sentry drug to inhibit the conversion of levodopa to dopamine. PHM2006 - medicinal chemistry for pharmaceutical professionals 10  It intentionally mimics the necessary structures of levodopa as a competitive antagonist to levodopa in the dopa decarboxylase enzyme. Carbidopa will not reduce levodopa’s effectiveness because it will still allow its conversion to dopamine in the brain, but will prevent its conversion outside the brain (in other parts in CNS). Dopamine cannot be directly administered into the body despite being an endogenous compound. It will just be digested/deactivated/decomposed by the biological mechanisms in the body. This is also why it needs to be a prodrug when administered into the body. Computers in Medicinal Chemistry Molecular mechanics: Studying drugs through computational analysis. High-throughput screening has favored computational analysis instead of bioassays. CADD used to be difficult to use because its results are often inconsistent with experiments. Atoms: Calculate the parameters of nucleus and electrons. Molecules: Calculate the parameters of atoms (electrons are often ignored) Space-filling representation of molecules shows how much space each atom takes. Computers model two aspects in its virtual screening: ligand and receptors. The things they screen: Structure, energy, binding. Energy calculation is done through modeling. Native conformation: The conformation in real-time situation (usually aqueous) It’s usually stable. Once we figure out the native conformation, we can calculate/study its properties. Highest binding affinity means the lowest energy required. While molecules may appear rigid, in computational analysis, we can stretch it, rotate it, and so on. Force fields describe how we can calculate these molecules’ energies. PHM2006 - medicinal chemistry for pharmaceutical professionals 11  Steric interaction: If two atoms are too close to each other, they will repel (Pauli repulsion). Unit 3: Metabolism and Targeting Pharmacokinetics and Drug Metabolism Drug and Drug Targets Overview Enzymes Receptors Signal Transduction Other Target Sites Nucleic Acids Unit 4: Drug Advancement and Distribution Small Molecule Drug Discovery Drug Distribution and Market PHM2006 - medicinal chemistry for pharmaceutical professionals 12