Lecture 21: Optimizing Drug-Target Interactions PDF

Principles of Drug Action/PHRM601 Optimizing Drug-Target Interactions Lecture #21  Medicinal Chemistry Drug-Target...

Principles of Drug Action/PHRM601 Optimizing Drug-Target Interactions Lecture #21  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  Optimizing drug-target interactions Learning Objectives Apply the concept of Pharmacophore for Drug Optimization. Strategies in Drug Design Modifications to Optimize Binding Interactions Define the terms bioisosterism and how it is important for drug optimization. Differentiate between classical and nonclassical bioisoteres.  1. Strategies in Drug Design Modification Strategies in Drug Design Modifications to Optimize Binding Interactions a) Vary alkyl substituents (Homologation) b) Extension, extra functional groups c) Chain expansion/contraction d) Ring expansion/contraction e) Ring variations f) Bioisosteres g) Simplification h) Rigidification To increase activity and reduce dose levels To increase selectivity and reduce side effects Different Formulations  1. Strategies in Drug Design Modification 1.1. Vary Alkyl substituents 1.1. Vary Alkyl Substituents (Homologation) Rationale: Alkyl group in lead compound may interact with hydrophobic region in binding site Vary length and bulk of group to optimize interaction LEAD COMPOUND ANALOGUE CH3 C H3C CH3 CH3 van der Waals Hydrophobic interactions pocket Homologation refers to the process of successively adding/removing methylene  1. Strategies in Drug Design Modification 1.1. Vary Alkyl substituents Rationale: Vary length and bulk of alkyl group to introduce selectivity N No Fit N CH3 Fit CH3 Steric N CH3 Fit Block Fit N CH3 Receptor 1 Receptor 2 Binding region for N harmacist Alert 1. Strategies in Drug Design Modification 1.1. Vary Alkyl substituents Examples: Selectivity of adrenergic agents for β-adrenoceptors over α-adrenoceptors OH H H Adrenaline HO N CH3 HO OH Salbutamol H H Ventolin) HOCH2 N C CH3 Anti-asthmatic) CH3 Agonist) CH3 HO CH3 ropranolol H Blocker, antihypertension) O N CH3 H Antagonist) OH (Vary Alkyl Substituents) a-Adrenoceptor H-Bonding region H-Bonding Ionic region bonding Van der Waals region bonding region H-Bonding region a-Adrenoceptor ADRENALINE b-Adrenoceptor The b-receptor is BIGGER in this region b-Adrenoceptor SALBUTAMOL a-Adrenoceptor SALBUTAMOL a-Adrenoceptor SALBUTAMOL Does not fit into a-receptor  1. Strategies in Drug Design Modification 1.1. Vary Alkyl substituents 1.2. Extension-Extra FGs 1.2. Structure Extension - Extra Functional Groups Rationale: To explore the target binding site for further binding regions to achieve additional binding interactions Unused Extra DRUG binding DRUG functional region group Drug Extension RECEPTOR RECEPTOR Binding regions Binding group  1. Strategies in Drug Design Modification harmacist Alert 1.1. Vary Alkyl substituents 1.2. Extension-Extra FGs Example: ACE Inhibitors Hydrophobic pocket Hydrophobic pocket Vacant CH3 CH3 EXTENSION O N O N N N H H O O CO2 CO2 O O Binding Binding site (I) site Enalaprilat (hypertensive Captopril emergencies, i.v.) The hydrophobic pocket is (First ACE optimally sized for a phenylalanine inhibitor, residue in this region.  1. Strategies in Drug Design Modification 1.1. Vary Alkyl substituents 1.2. Extension-Extra FGs 1.3. Chain Extension / Contraction 1.3. Chain extension /contraction Rationale : Useful if a chain is present connecting two binding groups Vary length of the chain to optimize interactions Weak Strong interaction interaction A B Chain A B extension HO RECEPTOR RECEPTOR O Binding regions N (CH2)n A & B Binding groups H HO Binding Binding Example: N-Phenethylmorphine group n=2 group HO Pharmacist Alert O N (CH2)n N-Phenethylmorphine H HO Binding Binding group n=2 group 50 to 100 times more potent Even small amounts can cause overdose (respiratory depression, confusion, and  1. Strategies in Drug Design Modification 1.3. Chain extension /contraction 1.4. Ring expansion/contraction 1.4. Ring Expansion/Contraction Rationale: To improve overlap of binding groups with their binding regions Ring expansion R R R R Better overlap with hydrophobic interactions Hydrophobic regions  1. Strategies in Drug Design Modification 1.3. Chain extension /contraction 1.4. Ring expansion/contraction Vary n to vary Example ring size Binding site O 2C (CH2)n N Binding site N Ph N H O CO2 O2C N N N O2C N Ph N H N O CO2 H O CO2 I Ph Binding regions Two interactions Three interactions Carboxylate ion out of Increased binding range Cilazaprilat  1. Strategies in Drug Design Modification 1.3. Chain extension /contraction 1.5. Ring Variations 1.4. Ring expansion/contraction 1.5. Ring Variations Rationale : Replace aromatic/heterocyclic rings with other ring systems Often done for patent reasons F SO2CH3 F SO2CH3 N X S N X Br CF3 DuP697 SC-58125 F SO2CH3 F SO2CH3 Core scaffold General structure for NSAIDS SC-57666  1. Strategies in Drug Design Modification 1.3. Chain extension /contraction 1.4. Ring expansion/contraction 1.5. Ring Variations Sometimes results in improved properties O O O Me HN HN HN N N N N N N N N Additional CO2tBu CO2tBu binding group Lead compound Nevirapine Examples N N N N OH N OH C C Cl Cl Ring F variation F Structure I UK-46245 (Antifungal agent) Improved selectivity  1. Strategies in Drug Design Modification 1.5. Ring Variations 1.6. Bioisosteres 1.6. Bioisosteres Replace the atom or functional group with a group of the same valency atoms (isostere) (same physiochemical property) e.g. OH replaced by SH, NH2, CH3 O replaced by S, NH, CH2 Leads to more controlled changes in steric (size)/electronic (polarity, electronic distribution, and bonding) properties (Rationale approach) May affect binding and/or stability Me Example Useful for SAR O NH Me H Replacing OCH2 with CH=CH, SCH2, and OH CH2CH2 eliminates activity Replacing OCH2 with NHCH2 retains activity Implies O involved in binding (HBA) Propranolol (b-blocker)  1. Strategies in Drug Design Modification 1.5. Ring Variations 1.6. Bioisosteres 1.6. Bioisosteres Substituents or groups that have chemical and physical similarities and produce broadly similar biological properties. – Important lead modification approach to attenuate toxicity or to modify the activity of a lead – may have a significant role in the alteration of pharmacokinetics of a lead. Classical bioisosteres: Atoms or ions, or molecules in which the peripheral layers of electrons can be considered to be identical. Nonclassical bioisosteres: Do not have the same number of atoms and do not fit the steric and electronic rules of classical isosteres, but do produce similar biological activity. 1. Strategies in Drug Design Modification 1.5. Ring Variations 1.6. Bioisosteres  1. Strategies in Drug Design Modification 1.5. Ring Variations 1.6. Bioisosteres Examples of Classical Bioisosteres Sterically hydrogen and fluorine are quite similar with their van der Waal’s radii being 1.2 and 1.35 Å. Fluorine is the most electronegative element in the periodic table. A classical example of hydrogen replacement by fluorine is development of anticancer agent 5-fluorouracil from uracil. Anticancer agent  1. Strategies in Drug Design Modification 1.5. Ring Variations 1.6. Bioisosteres Examples of Classical Bioisosteres Antihistamine and anticholinergic Antihistamine, sedative Drowsiness, not used anymore Isosteric substitution of thiophene for benzene and benzene for pyridine  1. Strategies in Drug Design Modification 1.5. Ring Variations Examples of Nonclassical Bioisosteres 1.6. Bioisosteres Do not have the same number of atoms and do not fit the steric and electronic rules of classical isosteres, but do produce similar biological activity. Replace a functional group with another group that retains the same biological activity Not necessarily the same valency 1.7. Simplification 1. Strategies in Drug Design Modification 1.6. Bioisosteres Rationale : 1.7. Simplification Lead compounds from natural sources are often complex and difficult to synthesize. Simplifying the molecule makes the synthesis of analogs easier, quicker and cheaper. Simpler structures may fit the binding site more easily and increase activity. Simpler structures may be more selective and less toxic if excess functional groups are removed. Retain pharmacophore Remove unnecessary functional groups HOOC OH OH Ph Drug NHMe Ph Drug NHMe Cl OMe harmacist Alert 1. Strategies in Drug Design Modification 1.6. Bioisosteres Example : Morphine Remove excess rings 1.7. Simplification HO HO HO O N CH3 N CH3 Me N CH3 H H H H H H Me HO Morphine Levorphanol Metazocine Potent analgesic Postoperative pain Excess functional groups Excess ring or migraines Me N CO2Me Et2NCH2CH2 O O C H O Local anesthetic O C COCAINE H PROCAINE otent stimulant and addictive NH2 Important binding groups retained Example: Cocaine Unnecessary ester removed Pharmacophore Complex ring system removed  2. Strategies in Drug Design Modification 2.6. Isosteres and Bio-isosteres 2.7. Simplification Disadvantages Oversimplification may result in decreased activity and selectivity Simpler molecules have more conformations More likely to interact with more than one target binding site May result in increased side effects  2. Strategies in Drug Design Modification 2.7. Simplification 2.8. Rigidification 2.8. Rigidification Endogenous lead compounds are often simple and flexible Fit several targets due to different active conformations Results in side effects single bond rotation + + Flexible chain Different conformations Strategy Rigidify molecule to limit conformations - conformational restraint Increases activity - more chance of desired active conformation being present Increases selectivity - less chance of undesired active conformations Disadvantage Molecule is more complex and may be more difficult to synthesize  2. Strategies in Drug Design Modification 2.7. Simplification 2.8. Rigidification H NH2Me H O O NH2Me H H BOND ROTATION I II O 2C H H NH2Me O O O H O 2C O H NH2Me H H RECEPTOR 1 RECEPTOR 2  2. Strategies in Drug Design Modification 2.7. Simplification 2.8. Rigidification Introducing Rings (Rigidification) Bonds within ring systems are locked and cannot rotate freely Test rigid structures to see which ones have retained active conformation rotatable bonds fixed bonds H H OH OH O O OH Rigidification O NH2Me NHMeRotatable H bonds HN HN CH3 CH3 FLEXIBLE MESSENGER RIGID MESSENGER NHMe Introducing rings Me H N X N X NHMe X CH3 X X X NHMe NMe Rotatable bond Rotatable bond Ring formation  Ring formation  2. Strategies in Drug Design Modification 2.7. Simplification 2.8. Rigidification Introducing rigid functional groups 'locked' bonds Flexible O chain C NH  2. Strategies in Drug Design Modification 2.7. Simplification 2.8. Rigidification Examples CO2H NH2 O Inhibits N Important binding groups HN N H platelet aggregation N guanidine flexible chain O Ar (I) Analogues diazepine ring system NH2 CO2H CO2H NH2 HN O O N HN N H N N O CH3 N Rigid N Rigid O Rigid III Ar Ar II  2. Strategies in Drug Design Modification 2.7. Simplification 2.8. Rigidification Example - Combretastatin (anticancer agent) Rotatable bond OCH3 OH H3CO Z-isomer H3CO H3CO OH E-isomer H3CO H3CO H3CO Less active OCH3 OCH3 OCH3 OH OH OCH3 OCH3 Combretastatin A-4 Combretastatin More active  Key Facts Drug Design Modifications to Optimize Binding Interactions a) Vary alkyl substituents (Homologation) b) Extension, extra functional groups c) Chain expansion/contraction d) Ring expansion/contraction e) Ring variations f) Bioisosteres (isosteres)/Classical or Nonclassical g) Simplification with keeping pharmacophore h) Rigidification