Download as PDF, PPTX
More Related Content
Drug design i
- 1. Drug design Improving targetinteractions (Pharmacodynamics)
- 2. Drug design -optimizing binding interactions •To increase activity and reduce dose levels •To increase selectivity and reduce side effects Strategies Vary alkyl substituents Vary aryl substituents Extension Chain extensions / contractions Ring expansions / contractions Ring variation Isosteres Simplification Rigidification Aim
- 3. Vary alkyl substituents Rationale: •Alkyl group in lead compound may interact with hydrophobic region in binding site • Vary length and bulk of group to optimise interaction ANALOGUE C CH3 CH3H3C van der Waals interactions LEAD COMPOUND CH3 Hydrophobic pocket
- 4. Rationale: Vary length andbulk of alkyl group to introduce selectivity Vary alkyl substituents Fit Fit N CH3 N CH3 Fit No Fit Steric Block N CH3 CH3 N Binding region for N Receptor 1 Receptor 2 Example: Selectivity of adrenergic agents for b-adrenoceptors over a- adrenoceptors
- 5. Vary alkyl substituents Propranolol (b-Blocker) OH ON H CH3 CH3 H Salbutamol (Ventolin) (Anti-asthmatic) HOCH2 HO H N C CH3 OH CH3 H CH3 Adrenaline HO HO H N CH3 OH H
- 6.
- 7.
- 8.
- 9.
- 10.
- 11. Vary alkyl substituents Syntheticfeasibility of analogues • Feasible to replace alkyl substituents on heteroatoms with other alkyl substituents • Difficult to modify alkyl substituents on the carbon skeleton of a lead compound.
- 12. Vary alkyl substituents Methods O R' DrugO H Drug O R" Drug Ether HBr a) NaH b) R"I N Me Drug N H Drug N R" Drug R R R Amine VOC-Cl R"I C OR Drug C OH Drug C OR" Drug O O O Ester HO- H+ R"OH
- 13. Vary alkyl substituents Methods O C Drug O R OHDrugO C Drug O R" Ester R"COClHO- NH C Drug O R NH2Drug NH C Drug O R" Amide R"COClH+ C NR2 Drug C OH Drug C NR2" Drug O O O Amide H+ HNR"2
- 14. Binding Region (H-Bond) Binding Region (forY) paraSubstitution Binding site H O Y meta Substitution Binding site O H Y Vary aryl substituents Vary substituents Vary substitution pattern Weak H-Bond Strong H-Bond (increased activity)
- 15. Vary aryl substituents Anti-arrhythmicactivity best when substituent is at 7-position Benzopyrans 6 7 8 O O NR MeSO2NH Vary substituents Vary substitution pattern
- 16. .. N O O NH2 Vary aryl substituents Notes •Binding strength of NH2 as HBD affected by relative position of NO2 • Stronger when NO2 is at para position Meta substitution: Inductive electron withdrawing effect Para substitution: Electron withdrawing effect due to resonance + inductive effects leading to a weaker base .. N O NH2 O N O NH2 O Vary substituents Vary substitution pattern
- 17. RECEPTOR Rationale: To exploretarget binding site for further binding regions to achieve additional binding interactions Extension - extra functional groups Unused binding region DRUG RECEPTOR DRUG Extra functional group Binding regions Binding group Drug Extension
- 18. Example: ACE Inhibitors Extension- extra functional groups EXTENSION Hydrophobic pocket Binding site N H N O CO2 O O CH3 Binding site N H N O CO2 O O CH3 (I) Hydrophobic pocket Vacant
- 19. Example: Nerve gasesand medicines Extension - extra functional groups Notes: • Extension - addition of quaternary nitrogen • Extra ionic bonding interaction • Increased selectivity for cholinergic receptor • Mimics quaternary nitrogen of acetylcholine Sarin (nerve gas) O P F O(CHMe2) CH3 Ecothiopate (medicine) O P S N CH3 H3C H3C OEt OEt Acetylcholine O N CH3 H3C H3C CH3 O O P S N CH3 H3C H3C OEt OEt
- 20. Example: Second-generation anti-impotencedrugs Extension - extra functional groups Notes: • Extension - addition of pyridine ring • Extra van der Waals interactions and HBA • Increased target selectivity ViagraN N CH3 S OO CH3 N HN O N N CH3 CH3 N N CH3 S OO CH3 N HN O N H N CH3 N N N CH3 S OO CH3 N HN O N H N CH3 N
- 21. Example: Antagonists fromagonists Extension - extra functional groups HO HO H N CH3 OH H Adrenaline OH O N H CH3 CH3 H Propranolol (b-Blocker) N HN NH2 Histamine N HN S H3C H N HN C N CH3 N HN S H3C H N HN C N CH3 Cimetidine (Tagamet) (Anti-ulcer)
- 22. Rationale: • Useful ifa chain is present connecting two binding groups • Vary length of chain to optimise interactions Chain extension / contraction RECEPTOR A B A B RECEPTOR Binding regions Binding groupsA & B Weak interaction Strong interaction Chain extension
- 23. Example: N-Phenethylmorphine Chain extension/ contraction Optimum chain length = 2 HO O HO N (CH2)n H Binding group Binding group HO O HO N (CH2)n H
- 24. Rationale: To improve overlapof binding groups with their binding regions Ring expansion / contraction Hydrophobic regions R R R R Ring expansion Better overlap with hydrophobic interactions
- 25. Example: Ring expansion /contraction Binding regions Binding site Binding site Vary n to vary ring size N H (CH2)n N N CO2O O2C Ph N N CO2O N H Ph O2C N H N N CO2O O2C Ph I Three interactions Increased binding Two interactions Carboxylate ion out of range
- 26. Rationale: • Replace aromatic/heterocyclicrings with other ring systems • Often done for patent reasons Ring variations General structure for NSAIDS X X Core scaffold S Br F SO2CH3 N N CF3 F SO2CH3 F SO2CH3 DuP697 F SO2CH3 SC-58125 SC-57666
- 27. Rationale: Sometimes results inimproved properties Ring variations Example: Structure I (Antifungal agent) Cl F C OHN N UK-46245 Improved selectivity Ring variation Cl F C OHN NN Structure I (Antifungal agent) Cl F C OHN N UK-46245 Improved selectivity Ring variation Cl F C OHN NN
- 28. Example - Nevirapine(antiviral agent) Ring variations N HN N O CO2 t Bu Lead compound N HN N N O CO2 t Bu N HN N N O Me Nevirapine Additional binding group N HN N N O CO2 t Bu
- 29. Selective for b- adrenoceptors overa-adrenoreceptors Example - Pronethalol (b-blocker) Ring variations R = Me Adrenaline R = H Noradrenaline HO HO C OH H NHR Pronethalol H N Me OH Me H
- 30. Rationale for isosteres: •Replace a functional group with a group of same valency (isostere) e.g. OH replaced by SH, NH2, CH3 O replaced by S, NH, CH2 • Leads to more controlled changes in steric / electronic properties • May affect binding and / or stability Isosteres and bio-isosteres
- 31. Useful for SAR Notes •Replacing OCH2 with CH=CH, SCH2, CH2CH2 eliminates activity • Replacing OCH2 with NHCH2 retains activity • Implies O involved in binding (HBA) Isosteres and bio-isosteres Propranolol (b-blocker) OH O H NH Me Me Propranolol (b-blocker) OH O H NH Me Me
- 32. Rationale for bio-isosteres: •Replace a functional group with another group which retains the same biological activity • Not necessarily the same valency Isosteres and bio-isosteres Example: Antipsychotics Improved selectivity for D3 receptor over D2 receptor Pyrrole ring = bio-isostere for amide group Sultopride EtO2S OMe O N H N Et DU 122290 EtO2S OMe N H N Et DU 122290 EtO2S OMe N H N Et
- 33. Rationale: • Lead compoundsfrom natural sources are often complex and difficult to synthesize • Simplifying the molecule makes the synthesis of analogues easier, quicker and cheaper • Simpler structures may fit the binding site better and increase activity • Simpler structures may be more selective and less toxic if excess functional groups are removed Simplification
- 34. Methods: • Retain pharmacophore •Remove unnecessary functional groups Simplification OH NHMe OMe HOOC Ph Cl Drug OH NHMePh Drug
- 35. Excess ring Methods: Simplification Example: HO O HO N CH3 H H Morphine HO NCH3 H H Levorphanol HO Me Me N CH3 H H Metazocine Remove excess rings Excess functional groups HO O HO N CH3 H H Morphine
- 36. Y C X H Chiral drug Y C X H Chiral drug Methods: Simplification Y N X Achiral drug Y C XY Achiral drug Remove asymmetric center Asymmetric center
- 37. Methods: Simplification Notes: • Simplification doesnot mean ‘pruning groups’ off the lead compound • Compounds usually made by total synthesis A OH OH N CH3 B N CH3 OH OH C OH OH N CH3 D N CH3H OH OH GLIPINE OH CH3 OH H3C N CH3 Simplify in stages to avoid oversimplification Pharmacophore GLIPINE OH CH3 OH H3C N CH3
- 38. Example: •Important binding groupsretained •Unnecessary ester removed •Complex ring system removed Simplification COCAINE N H O Me C CO2Me H O PROCAINE C NH2 O O Et2NCH2CH2 Pharmacophore COCAINE N H O Me C CO2Me H O PROCAINE C NH2 O O Et2NCH2CH2
- 39. Disadvantages: • Oversimplification mayresult 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 Simplification
- 40. Note • Endogenous leadcompounds are often simple and flexible • Fit several targets due to different active conformations • Results in side effects Rigidification 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 synthesise Flexible chain single bond rotation + + Different conformations
- 41. Rigidification BOND ROTATION O H O2C RECEPTOR1 O H O2C RECEPTOR 2 O H H NH2Me O NH2Me H H I O NH2Me H H II O H H NH2Me
- 42. Methods - Introducerings • Bonds within ring systems are locked and cannot rotate freely • Test rigid structures to see which ones have retained active conformation Rigidification FLEXIBLE MESSENGER O H H NH2Me rotatable bonds RIGID MESSENGER O NHMe H fixed bonds
- 43. Rigidification H NX CH3 X NHMe X NHMe X Me N X NMe X NHMe Introducing rings Methods- Introduce rings • Bonds within ring systems are locked and cannot rotate freely • Test rigid structures to see which ones have retained active conformation
- 44. Rigidification Methods - Introducerings • Bonds within ring systems are locked and cannot rotate freely • Test rigid structures to see which ones have retained active conformation OH OH HN CH3 OH O HN CH3 Rigidification Rotatable bonds
- 45. Methods - Introducerigid functional groups Rigidification Flexible chain C NH O 'locked' bonds
- 46. N N CO2H O Ar N O CH3 HN NH2 III Rigid Examples Rigidification Inhibits platelet aggregation N N CO2H N H HN NH2 O O Ar guanidine diazepine ring system flexiblechain (I) N N CO2H O O N H HN NH2 Ar II Analogues Important binding groups N N CO2H N H HN NH2 O O Ar guanidine diazepine ring system flexible chain (I) Rigid Rigid N N CO2H O Ar N O CH3 HN NH2 III
- 47. Examples - Combretastatin(anticancer agent) Rigidification More active Less active Rotatable bond H3CO H3CO OCH3 OCH3 OH Combretastatin A-4 Z-isomer OH H3CO H3CO OCH3 OCH3 OH Combretastatin H3CO H3CO OCH3 OCH3 OH E-isomer
- 48. Methods - StericBlockers Rigidification YX Flexible side chain X Y Coplanarity allowed X Y CH3 Orthogonal rings preferred YX CH3 steric block Introduce steric block X Y CH3 H steric clash Introduce steric block X CH3 Y Unfavourable conformation Steric clash
- 49. Steric clash Rigidification Increase in activity Activeconformation retained Serotonin antagonistN H N N O CF3 OMe N H Introduce methyl group N H N N O CF3 OMe N CH3 H N H N N O CF3 OMe N CH3 H orthogonal rings Methods - Steric Blockers
- 50. Steric clash Rigidification D3 AntagonistInactive - active conformation disallowed free rotation N (CH2)4 H N O CF3O2SO I N (CH2)4 H N O CF3O2SO Me II H Methods – Steric Blockers
- 51. N N CH3 N HN O Rigidification Identification ofan active conformation by rigidification
- 52. Rigidification Identification of anactive conformation by rigidification Planar conformation
- 53. Rigidification Identification of anactive conformation by rigidification Orthogonal conformation
- 54. Rigidification Identification of anactive conformation by rigidification CYCLISATION
- 55. Rigidification Identification of anactive conformation by rigidification STERIC HINDRANCE