Annotated Lecture 6 - Drug Design Optimizing Target Interactions.pptx

This is a slide deck about drug design. This presentation was created during my pharmacology class and it was based on my Medicinal Chemistry by Graham Patrick 6th Edition. It is an adaptation and not a transcript of the textbook chapter 13.

1. DRUG DESIGN OPTIMIZING TARGET INTERACTIONS Patrick: An Introduction to Medicinal Chemistry 6e Chapter 13

2. DRUG DESIGN AND DEVELOPMENT Stages 1) Identify target disease 2) Identify drug target 3) Establish testing procedures 4) Find a lead compound 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 7) Drug design- optimizing target interactions 8) Drug design - optimizing pharmacokinetic properties 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials

3. 7. DRUG DESIGN - OPTIMIZING BINDING INTERACTIONS Aim - To optimize binding interactions with target 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 Reasons

4. 7.1 Vary Alkyl Substituents Rationale An alkyl group in the lead compound may interact with a hydrophobic region in the binding site Vary the length and/or bulk of the group to optimise interaction Van der Waals interactions Hydrophobic pocket

5. Rationale Varying the length and/or bulk of alkyl group may introduce selectivity between two different binding sites 7.1 Vary Alkyl Substituents Binding region for N Receptor 1 Receptor 2 Fit Fit No fit Fit Steric block Example Selectivity of adrenergic agents for b -adrenoceptors over a -adrenoceptors

6. 7.1 Vary Alkyl Substituents Propranolol ( b -Blocker) Salbutamol ( Ventolin ) (Anti-asthmatic) Adrenaline

7. a - Adrenoceptor H-Bonding region H-Bonding region H-Bonding region Van der Waals bonding region Ionic bonding region

8. ADRENALINE a - Adrenoceptor

9. a - Adrenoceptor

10. b -Adrenoceptor ADRENALINE

11. SALBUTAMOL b -Adrenoceptor

12. a - Adrenoceptor SALBUTAMOL

13. a - Adrenoceptor SALBUTAMOL

14. 7.1 Vary Alkyl Substituents Synthetic feasibility of analogues Feasible to replace alkyl substituents on heteroatoms with other alkyl substituents Difficult to modify alkyl substituents attached to the carbon skeleton of a lead compound. Total synthesis usually required to vary alkyl substituents that are attached to the carbon skeleton

15. 7.1 Vary Alkyl Substituents Methods

16. 7.1 Vary Alkyl Substituents Methods

17. 7.2 Vary Aryl Substituents Vary substituents Vary substitution pattern Binding Region (H-Bond) Binding Region (for Y) para Substitution meta Substitution Weak H-Bond Strong H-Bond (increased activity)

18. 7.2 Vary Aryl Substituents Anti-arrhythmic activity is best when the substituent is at the 7-position Vary substituents Vary substitution pattern Benzopyrans

19. 7.2 Vary Aryl Substituents Notes Binding strength of NH 2 as HBD affected by relative position of NO 2 Stronger when NO 2 is at para position Amine N is a weak HBA due to effects shown Meta substitution: Inductive electron-withdrawing effect Para substitution: Electron-withdrawing effect due to resonance + inductive effects leading to a weaker base Vary substituents Vary substitution pattern

20. RECEPTOR Rationale To explore target binding site for further binding regions to achieve additional binding interactions 7.3 Extension - Extra Functional Groups Unused binding region DRUG RECEPTOR DRUG Extra functional group Binding regions Binding groups Drug Extension

21. Binding site Example ACE Inhibitors 7.3 Extension - Extra Functional Groups Hydrophobic pocket Vacant Hydrophobic pocket Binding site EXTENSION

22. Example Nerve agents and medicines 7.3 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) Acetylcholine Ecothiopate (medicine)

23. Example Antagonists from agonists 7.3 Extension - Extra Functional Groups Adrenaline Histamine Propranolol ( b -Blocker) Cimetidine (Tagamet) (Anti-ulcer)

24. Rationale Useful if a chain is present connecting two binding groups Vary length of chain to optimize interactions 7.4 Chain Extension / Contraction RECEPTOR A B A B RECEPTOR Binding regions Binding groups A & B Weak interaction Strong interaction Chain extension

25. Example N - Phenethylmorphine 7.4 Chain Extension / Contraction Optimum chain length n = 2 Binding group Binding group

26. Rationale To improve overlap of binding groups with their binding regions 7.5 Ring Expansion / Contraction Hydrophobic regions R R R R Ring expansion Better overlap with hydrophobic interactions

27. Binding site Binding regions Binding site Example – Design of the ACE inhibitor cilazaprilat 7.5 Ring Expansion / Contraction Vary n to vary ring size Cilazaprilat Three interactions Increased binding Lead compound (I) Two interactions Carboxylate ion out of range

28. Rationale Replace aromatic/heterocyclic rings with other ring systems Often done for patent reasons 7.6 Ring Variations General structure for NSAIDS Core scaffold

29. Rationale 7.6 Ring Variations Example Structure I (Antifungal agent) UK-46245 Improved selectivity Ring variation Ring variation sometimes results in improved properties

30. Example - Nevirapine (antiviral agent) 7.6 Ring Variations Additional binding group Lead compound Nevirapine

31. Antagonist Example - Pronethalol ( b -blocker) 7.6 Ring Variations Agonist R = Me Adrenaline R = H Noradrenaline Pronethalol

32. Rationale for isosteres Replace a functional group with a group of same valency (isostere) e.g. OH replaced by SH, NH 2 , CH 3 e.g. O replaced by S, NH, CH 2 Leads to more controlled changes in steric/electronic properties May affect binding and / or stability 7.7 Isosteres and Bio-isosteres

33. Useful for SAR Notes Replacing OCH 2 with CH=CH, SCH 2 , CH 2 CH 2 eliminates activity Replacing OCH 2 with NHCH 2 retains activity Implies O involved in binding (HBA) 7.7 Isosteres and Bio-isosteres Propranolol ( b -blocker)

34. Rationale for bio- isosteres Replace a functional group with another group which retains the same biological activity Not necessarily the same valency 7.7 Isosteres and Bio-isosteres Example Antipsychotics Improved selectivity for D 3 receptor over D 2 receptor Pyrrole ring = bio- isostere for amide group Sultopride DU 122290

35. Rationale Lead compounds from natural sources are often complex and difficult to synthesise Simplifying the molecule makes the synthesis of analogues easier, quicker, and cheaper Simpler structures may fit the binding site easier and increase activity Simpler structures may be more selective and less toxic if excess functional groups are removed 7.8 Simplification

36. Methods Retain pharmacophore Remove unnecessary functional groups and rings 7.8 Simplification Remove excess functional groups

37. Excess functional groups Analgesic pharmacophore retained Analgesic pharmacophore Analgesic pharmacophore retained Excess ring 7.8 Simplification Example Notes Morphine, levorphanol and metazocine are all analgesics Analgesic pharmacophore is retained despite simplification Levorphanol Metazocine

38. Methods 7.8 Simplification Remove asymmetric centres Asymmetric centre Chiral drug Achiral drug Chiral drug Achiral drug

39. Methods 7.8 Simplification Notes Simplification does not mean ‘pruning groups’ off the lead compound Compounds usually made by total synthesis Simplify in stages to avoid oversimplification Pharmacophore GLIPINE

40. Example Important binding groups retained Unnecessary ester removed Complex ring system removed 7.8 Simplification Pharmacophore PROCAINE COCAINE

41. Example 7.8 Simplification Asperlicin (CCK antagonist) Possible lead for treating panic attacks Devazepide Excess rings removed Benzodiazepine Indole

42. 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 7.8 Simplification

43. Target binding site

44. Target binding site

45. Target binding site Rotatable bonds

46. Target binding site Rotatable bonds

47. Target binding site Rotatable bonds

48. Different binding site leading to side effects Rotatable bonds

49. Oversimplification of opioids 7.8 Simplification

50. MORPHINE SIMPLIFICATION C C C C C C O N

51. LEVORPHANOL SIMPLIFICATION C C C C C C O N

52. LEVORPHANOL SIMPLIFICATION C C C C C C O N

53. METAZOCINE SIMPLIFICATION C C C C C C O N

54. C C C C C C O N OVER SIMPLIFICATION

55. C C C C C C O N OVER SIMPLIFICATION TYRAMINE

56. C C C C C C O N OVER SIMPLIFICATION AMPHETAMINE

57. Note Endogenous lead compounds are often simple and flexible Fit several targets due to different active conformations Results in side effects 7.9 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 + +

58. RECEPTOR 2 - O 2 C RECEPTOR 1 O 2 C - 7.9 Rigidification Bond rotation

59. Methods - Introduce rings Bonds within ring systems are locked and cannot rotate freely Test rigid structures to see which ones have retained active conformation 7.9 Rigidification Rotatable bonds Flexible messenger Fixed bonds Rigid messenger

60. 7.9 Rigidification Methods - Introduce rings Bonds within ring systems are locked and cannot rotate freely Test rigid structures to see which ones have retained active conformation

61. 7.9 Rigidification Rigidification Rotatable bonds Methods - Introduce rings Bonds within ring systems are locked and cannot rotate freely Test rigid structures to see which ones have retained active conformation

62. Rotatable bond

63. Rotatable bond Ring formation

64. Ring formation

65. Methods - Introduce rigid functional groups 7.9 Rigidification Flexible chain

66. Rigid Rigid Important binding groups Rigid Example – Platelet inhibitors 7.9 Rigidification Inhibits platelet aggregation Analogues Guanidine Flexible chain Diazepine ring system

67. Example - Combretastatin (anticancer agent) 7.9 Rigidification More active Less active Rotatable bond Combretastatin E -Isomer Z -Isomer Combretastatin A-4

68. Methods - Steric Blockers 7.9 Rigidification Flexible side chain Coplanarity allowed Steric block Introduce steric block Steric clash Introduce steric block Steric clash Orthogonal rings preferred Unfavourable conformation

69. Steric clash 7.9 Rigidification Increase in activity Active conformation retained Methods - Steric Blockers Example – Serotonin antagonists Introduce methyl group Orthogonal rings

70. Steric clash 7.9 Rigidification D 3 Antagonist Steric clash when rings coplanar Preferred conformation has rings orthogonal Structure II is inactive Implies active conformation has rings coplanar Methods - Steric Blockers Note Steric blocking may disallow an active conformation instead of favouring it Example – Dopamine antagonists Free rotation

71. N N CH 3 N H N O 7.9 Rigidification Identification of an active conformation by rigidification

72. 7.9 Rigidification Identification of an active conformation by rigidification N N CH N H N O 3

73. 7.9 Rigidification Identification of an active conformation by rigidification N N CH N H N O 3

74. 7.9 Rigidification Identification of an active conformation by rigidification Planar conformation

75. 7.9 Rigidification Identification of an active conformation by rigidification Orthogonal conformation

76. CYCLISATION 7.9 Rigidification Identification of an active conformation by rigidification Rigidify molecule by introducing an extra ring linking these positions

77. 7.9 Rigidification Identification of an active conformation by rigidification CYCLISATION

78. 7.9 Rigidification Identification of an active conformation by rigidification CYCLISATION Locked into planar conformation

79. STERIC HINDRANCE 7.9 Rigidification Identification of an active conformation by rigidification Introduce methyl substituent as conformational blocker

80. 7.9 Rigidification Identification of an active conformation by rigidification STERIC HINDRANCE Introduce methyl substituent as conformational blocker

81. 7.9 Rigidification Identification of an active conformation by rigidification STERIC HINDRANCE

82. 7.9 Rigidification Identification of an active conformation by rigidification STERIC HINDRANCE

83. 7.9 Rigidification Identification of an active conformation by rigidification STERIC HINDRANCE Locked into orthogonal conformation

84. 7.10 Structure-based drug design Procedure Crystallise the target protein with a bound ligand Acquire the structure by X-ray crystallography Download to a computer for molecular modelling studies Identify the binding site Identify the binding interactions between ligand and target Identify vacant regions for extra binding interactions Remove the ligand from the binding site in silico ‘Fit’ analogues into the binding site in silico to test binding capability Identify the most promising analogues Synthesise and test for activity Crystallise a promising analogue with the target protein and repeat the process Strategy Carry out drug design based on the interactions between the lead compound and the target binding site

85. Ligand in binding site

86. The design of novel agents based on a knowledge of the target binding site 7.11 De Novo Drug Design Procedure Crystallise the target protein with a bound ligand Acquire the structure by X-ray crystallography Download to a computer for molecular modelling studies Identify the binding site Remove the ligand in silico Identify potential binding regions in the binding site Design a lead compound to interact with the binding site Synthesise the lead compound and test it for activity Crystallise the lead compound with the target protein and identify the actual binding interactions Optimise by structure-based drug design