Drug-Target Interactions Lecture 19 PDF

Medicinal Chemistry Drug-Target Drugs Targets Drug Interactions...

Medicinal Chemistry Drug-Target Drugs Targets Drug Interactions Discovery Development & Optimiza sicochemical Property of Drug-1 Enzymes Forces in Drug- Functional Group (FG) Receptor Target Acidity and Basicity of FG Optimization of Drug Interactions SAR, Bioisosterism, Rigidification Enzyme and Discovery & Design sicochemical Property of Drug-2 Receptor Peptide/Protein based drug - Salt and Solubility Interactions Combinatorial & Parallel Chemistry - Chirality Use of Computers in Drug Design (Molecular Modelling, QSAR, AI) Physicochemical Properties of Drug Absorption and Membrane Drug Drug Nanomedicin transporters Metabolism e Examples of Drug Classes  LEARNING OBJECTIVES Explain with examples of Reversible, Irreversible, and Transition- State Inhibitors. What are Allosteric Inhibitors and how do they bind to a site different than the active site? How to calculate IC50 from the enzyme inhibition curve?  Drug-Target Interactions Forces involved in Drug-Receptor Interactions Enzyme and Receptor Inhibitors Lecture 19  Drug-Target Bonding Interactions Forces Involved in the Drug-Receptor Interactions Two major types of bonding: A. Covalent Bonding B. Non-Covalent Bonding  Forces Involved in the Drug- Receptor Interactions The biological activity of a drug is related to the stability of the drug-receptor complex. This stability is commonly measured by how difficult it is for the complex to dissociate, which is measured by its KD, the dissociation constant for the drug-receptor complex at equilibrium. The smaller the KD, the larger the concentration of the drug-receptor complex, the more stable is that complex, and the greater is the affinity of the drug for the receptor.  Drug Bonding Interactions A. Covalent Binding A. Covalent bonding interactions – Irreversible – Example of drugs: Aspirin (COX inhibitor), Chlorambucil (chemotherapeutic alkylating agents against tumors) – Strongest bond, generally worth from 40 to 140 kcal/mol in stability (typical C—C bond length = 1.54 Å) – Seldom formed by drug-receptor interactions, except with some enzymes and DNA. – Examples of covalent binding: Alkylation, Acylation, and Phosphorylation reactions Pharmacist Alert Anticancer Alkylating agents Nitrogen Mustards: Mechlorethamine Chlorambucil, Melphalan, Cyclophosphamide Crosslinking X X X X Nu Nu Nu Nu Nu Nu Nu Nu Intrastrand crosslinking Interstrand crosslinking Form covalent bonds to nucleophilic groups in DNA (e.g. 7-N of guanine) Prevent replication and transcription Can cause interstrand and intrastrand crosslinking if two electrophilic groups are present Alkylation of nucleic acid bases can result in miscoding  Pharmacist Alert Many antitumor agents act by alkylating of the DNA bases, thereby preventing hydrogen bonding. This disrupts the double helix and destroys the DNA.  Drug Bonding Interactions B. Non-Covalent Bonding B. Non-Covalent Bonding Weak noncovalent interactions; Reversible Hydrophobic Interactions Ionic Interactions  Drug Bonding Interactions B. Non-Covalent Bonding Example of a non-covalent interaction: Acetylcholine- Non-Covalent Bond Energy Muscarinic Cholinergic Receptor  Drug Bonding Interactions B. Non-Covalent Bonding B1. Ionic interactions B1. Electrostatic or Ionic interactions The strength of the ionic interaction is inversely proportional to the distance between the two charged groups Stronger interactions occur in hydrophobic environments Ionic bonds are the most important initial interactions as a drug enters the binding site O Drug Drug NH3 O O H3N Target Target O O H O N Example: Advil (Ibuprofen) H H  Drug Bonding Interactions B. Non-Covalent Bonding B2. Dipole Interactions B2: Dipole Interactions As a result of the greater electronegativity of atoms such as oxygen, nitrogen, sulfur, and halogens relative to that of carbon, C-X bonds in drugs and receptors, where X is an electronegative atom, will have an asymmetric distribution of electrons; this produces electronic dipoles. These dipoles in a drug molecule can be attracted by ions (ion-dipole interaction) or by other dipoles (dipole-dipole interaction) in the receptor, provided charges of opposite signs are properly aligned. Because the charge of a dipole is less than that of an ion, a dipole-dipole interaction is weaker than an ion-dipole interaction.  Drug Bonding Interactions B. Non-Covalent Bonding B.2.1.: Dipole Interactions B.2.1. Ion-dipole interactions Ion-dipole Occur where the charge on one molecule interacts with the dipole moment of another Stronger than a dipole-dipole interaction Strength of interaction falls off less rapidly with distance than for a dipole-dipole interaction R O d- C d+ R R O d- C d+ O H3N O C R Binding site Binding site  Drug Bonding Interactions B. Non-Covalent Bonding B2.2.: Dipole Interactions B.2.2. Dipole-dipole interactions d- O Dipole moment d+ C R R Localized dipole moment R O C R Binding site Binding site  Drug Bonding Interactions B. Non-Covalent Bonding B(ii): Dipole Interactions Example: Insomnia drug Zalepan (Sonata) provides a Gº = -1 to -7 kcal/mol  Drug Bonding Interactions B.2.3. Hydrogen Bonding B. Non-Covalent Bonding B2.3.: Dipole Interactions Hydrogen Bonding A type of dipole-dipole interaction formed between exchangeable protons. Hydrogen bonds are a type of dipole-dipole interaction formed between the proton of a group X-H, where X is an electronegative atom, and other electronegative atoms (Y), containing a pair of nonbonded electrons. The interaction is denoted as a dotted line, -X-H…..Y-, to indicate that a covalent bond between X and H still exists, but that an interaction between H and Y also occurs. There are intramolecular and intermolecular hydrogen bonds. Pharmacist Alert Hydrogen Bondings are important for biological activity (Changes pKa?) Intramolecular hydrogen binding may mask the binding of a group with pharmacological activity. Methyl salicylate is an active ingredient in many muscle pain remedies, but a weak antibacterial agent. The corresponding para- isomer is a more potent antibacterial agent since the O-H group does not have intramolecular hydrogen bonding (Because the O-H Hydrogen bonds are essential in maintaining the structural integrity of the secondary structure (-helix and -sheet conformation of peptides and proteins and double helix of DNA).  FG in Protein FG in Amino Acids (Aas) All of you know AAs. Correct? There are 20 amino acids that all have the same basic structure. FG in Protein  FG in Protein Peptides  -helix Hydrogen bonding in antiparallel and parallel β-sheets The β-turn showing hydrogen bonding between the first and third peptide bonds. Examples of hydrogen bonding between water and hypothetical drug molecules. Common Organic Functional Groups and Their Hydrogen-Bonding Potential Functional Number of Groups Potential H-bonds R–OH 3 Ketone 2 R–NH2 3 Secondary amine 2 Tertiary amine 1 Ester 2 Foye's Principles of Medicinal Chemistry, 8e, 2019  B.3. Van der Waals Drug Bonding Interactions B. Non-Covalent Bonding Interactions (London Forces) B.3. Van der Waals interactions Very weak interactions Occur between hydrophobic regions of the drug and the target Transient areas of high and low electron densities cause temporary dipoles Interactions drop off rapidly with distance The drug must be close to the binding region for interactions to occur The overall contribution of van der Waals interactions can be crucial to binding DRUG Hydrophobic regions d+ d- Transient dipole on drug d+ d- van der Waals interaction d- d+ Binding site  Hydrophobic Interactions Alignment of two hydrophobic groups. Increase in entropy Decreased free energy that stabilizes the drug-receptor complex. Example of potential multiple drug-receptor interactions  Forces involved in Drug-Receptor Interactions Conclusions Types of intermolecular binding interactions – Recognize each type and characteristics – Noncovalent Interactions are generally weak, should know the relative strength – Cooperativity by several types of interactions is critical. – The effect of cooperativity in several rather weak interactions may combine to produce a strong interaction. – Charged groups bind more tightly than polar groups, which bind more tightly than nonpolar groups (per single interaction) Ion-ion > ion-dipole > dipole-dipole > van der Waals interaction  Enzymes Why inhibit enzymes? Inhibition Many diseases arise from a deficiency or excess of a specific metabolite in the body, from an infestation of a foreign organism, or from aberrant cell growth. The situation can be normalized by inhibiting a specific enzyme Any compound that slows down or blocks enzyme catalysis is an enzyme inhibitor Pharmacist Alert Enzyme targets for useful medications Antibacterial agents Dihydropteroate synthetase, transpeptidase Antiviral agents HIV reverse transcriptase, HIV protease, viral DNA polymerase Anti-inflammatory agents Cyclooxygenase Cholesterol lowering agents HMG-CoA reductase Antidepressants Monoamine oxidase Anticancer agents Tyrosine kinase, dihydrofolate reductase, thymidylate synthase, aromatase, etc Pharmacist Alert More Enzyme targets for useful medications Antihypertensive agents Renin, angiotensin converting enzyme Treatment of male erectile dysfunction Phosphodiesterase Anti-gout agents Xanthine oxidase Alzheimers disease Cholinesterases Diuretics Carbonic anhydrase  Enzymes E Inhibitors Enzyme Inhibitors (EIs) A. Reversible Enzyme Inhibitors B. Irreversible Enzyme Inhibitors C. Allosteric Inhibitors D. Transition State Analogs  EIs A. Reversible EIs A. Reversible Enzyme Inhibitors Any compound that slows down or blocks enzyme catalysis Inhibitor binds reversibly to the active site Enzyme is not available for catalysis when the inhibitor is bound Substrate is blocked from the active site Increasing substrate concentration reverses inhibition Inhibitor likely to be similar in structure to substrate, product, or cofactor S I I EE E  EIs A. Reversible EIs Competitive and Non-competitive inhibition Competitive Non-Competitive Inhibition Inhibition Sulfonamides Diuretics Kinase inhibitors  EIs Pharmacist Alert A. Reversible EIs Example: Reversible EI: Sulfa Drugs Pterin  Sulfa drugs Prontosil was converted by reduction to the active antibacterial agent, namely, p-aminobenzenesulfonamide (also called sulfanilamide). Sufanilamide inhibits folic acid biosynthesis by inhibiting dihyropteroate synthetase that catalyzes the synthesis of dihydrofolate from diphosphate and p-aminobenzoic acid. Because of the structural similarity of sulfanilamide to P- aminobenzoic acid, it is a potent competitive inhibitor of dihyropteroate synthetase. Coadministration of PABA and sulfanilamide prevents the antibacterial action of the drug (reversible inhibitor)  EIs B. Irreversible Inhibitors B. Irreversible EIs X Covalent Bond X OH OH O Irreversible inhibition Inhibitor binds irreversibly to the active site A covalent bond formed between the drug and the enzyme Substrate is blocked from the active site Increasing substrate concentration does not reverse the inhibition Inhibitor likely to be similar in structure to the substrate  EIs Pharmacist Alert C. Irreversible EIs Examples – Nerve gases, Penicillins, Disulfuram, Cephalosporins, Proton Pump Inhibitor, Orlistat Orlistat C6H13 C11H23 O O O C11H23 O O C6H13 NHCHO C11H23 O But NHCHO O C6H13 But O O OH O H O O O O But NHCHO Ser Ser Ser Pancreatic lipase Pancreatic lipase Pancreatic lipase Orlistat is an anti-obesity drug that inhibits pancreatic lipase The enzyme is blocked from digesting fats in the intestine Fatty acids and glycerol are less absorbed as a result Leads to reduced biosynthesis of fat in the body  EIs C Allosteric Inhibitors C. Allosteric Inhibitors Active site Active site unrecognisable Induced ACTIVE SITE fit (open) Enzyme ENZYME (open) Enzyme ENZYME Allosteric binding site Allosteric inhibitor Inhibitor binds reversibly to the allosteric site Intermolecular bonds are formed Induced fit alters the shape of the enzyme Active site is distorted and is not recognized by the substrate Increasing substrate concentration does not reverse the inhibition Inhibitor is not similar in structure to the substrate  EIs D. Transition-state Inhibitors D. Transition-state Is Drugs designed to mimic the transition state of an enzyme- catalyzed reaction Transition-state inhibitors are likely to bind more strongly than drugs mimicking the substrate or product Transition states are high energy, transient species and cannot be isolated or synthesized Drug design can be based on reaction intermediates which are closer in character to transition states than substrates or products Design a drug that mimics the stereochemistry and binding properties of the reaction intermediate, but is stable  6. EIs 6D. Transition-state Is Example: Renin inhibitors Inhibitor Angiotensin converting Renin enzyme (ACE) Angiotensinogen Angiotensin I Angiotensin II Renin inhibitors block synthesis of angiotensin I and II Angiotensin II constricts blood vessels and raises blood pressure Renin inhibitors act as antihypertensives (lower blood pressure)  EIs D. Transition-state Is Example: Renin inhibitors Reaction mechanism Tetrahedral intermediate R1 R1 R1 H Substrate H + N N H2N CO2H O O R2 R2 O R2 H H O H H H H H O O O O O O O O O O O O Asp Asp Asp Asp Asp Asp Renin Renin Renin Renin Two aspartyl residues involved in enzyme-catalyzed reaction Tetrahedral intermediate involved  EIs B. Transition-state Inhibitors Example: Renin inhibitors: Aliskiren MeO CHMe2 Protein H N MeO O O O Protein HO OH H2N N NH2 Reaction H Me Me intermediate OH CHMe2 Hydroxyethylene transition-state mimic Aliskiren contains a hydroxyethylene transition-state mimic Mimics the tetrahedral geometry of the reaction intermediate Mimics one of the hydroxyl groups (binding group) Stable - no leaving group present Other Transition-state inhibitors (Statins, Protease Inhibitors, ACE inhibitors)  7. IC50 7. IC50 IC50 = concentration of inhibitor required to reduce enzyme activity by 50%. IC50 is only measured at a single substrate concentration The IC50 is approximately 100 nM EC50 value The concentration of inhibitor required to reduce a particular cellular effect by 50% Uses Whole cell or whole tissue (cellular effect) Includes transport and various other in vivo parameters  Key Points Basic properties of enzymes, e.g. activation energy, enzyme theory, acid-base, covalent catalysis, IC50, an example of EIs. Competitive inhibitors bind to the active site and compete with either the substrate or cofactor Reversible inhibitors bind through intermolecular forces only Irreversible inhibitors make a covalent bond with enzymes (suicide!) Allosteric inhibitors bind to a site different than the active site. Alter the shape of the enzyme such that catalysis does not occur Transition State Analogs: Transition state analogs are molecules designed to mimic the high-energy transition state of a reaction. The activity of different enzyme inhibitors can be compared by measuring IC50.