Structure activity relation ship

medical chemistry , sar

1. Structure Activity Relationship Dr AKSHIL 22-04-2016 1

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4. Medicinal chemistry is a chemistry-based discipline, involving aspects of biological, medical and pharmaceutical sciences. It is concerned with the invention, discovery, design, identification and preparation of biologically active compounds, the study of their metabolism, the interpretation of their mode of action at the molecular level and the construction of structure-activity relationships (SARs).

5. Structure activity relationship (SAR) SAR is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of the dependence of biological effects of a chemical upon its molecular structure. Molecular structure and biological activity are correlated by observing the results of systematic structural modification on defined biological endpoints. 22-04-2016 5

6. Determination of the chemical groups responsible for evoking a target biological effect in the organism. Quantitative SARs (QSAR)as a special case of SARs (when relationships become quantified) 22-04-2016 6

7. 7 Crude drug Structure Ligand binding Receptor Biological response 22-04-2016 7

8. 8 WHY SAR Exist? The interaction of the drug molecule with protein depends on its chemical structure NEED OF SAR STUDY A study of the structure–activity relationship is mainly done by lead molecule. It is used to determine pharmacophore, unwanted side effects To develop a new drug that has increased activity. 22-04-2016

9. 9 Cont.….. To determine some different activity from an existing drug To fewer unwanted side effects To know the changes in pharmacological properties by performing minor changes in the drug molecule 22-04-2016

10. QSAR Attempts to find consistent relationship between the variations in the values of molecular properties & the biological activities for a series of compounds so that these “rules” can be used to evaluate new chemical entities. 3D QSAR –most powerful technique available for analog – based drug design. 22-04-2016 10

11. History of Medicinal Chemistry Early investigations of natural products In the so-called pre-scientific era Natural products having a history as folk remedies were in use. Fore examples, opium, belladonna, cinchona bark, etc. Many drugs originally used as folk remedies, nowadays, have been abandoned.

12. In the late eighteenth and early nineteenth centuries, chemical experimentation led ultimately to its use in the discovery of new drugs. In 1853, Henry How conceived the idea that functional groups in natural products might be modified by chemical reagents. He heated morphine with methyl iodide, hoping to convert the alkaloid to codeine. He obtained, however, a new substance of the quaternary salt of morphine.

13. In 1898 , the first commercially available semisynthetic morphine derivative (ethyl ether) was introduced as a cough sedative in preference to codeine or other opiates. Meanwhile, diacetylmorphine was introduced as a safer pain reliever than morphine. It quickly became popular throughout the world. Four years passed before its addictive properties of heroin were recognized. Laws were later passed by governments to restrict its use.

14. During the 1840s , the first use of synthetic organic chemicals were introduced for anesthesia during a tooth removal, such as nitrous oxide, ether, and chloroform. In 1864 , barbituric acid had been synthesized as a useful hypnotic.

15. In 1875 , salicylic acid was introduced as a possible cure for typhoid fever . It was found to be an effective antipyretic. In 1899 , Aspirin (Acetyl salicylic acid) was marketed as an antipyretic without the unpleasant side effects. This indicated that the chemical structures from natural products were changed into better drugs. Medicinal Chemistry began.

16. Selectivity of Drug Action and Drug Receptors Similar molecules exert similar biological actions in a qualitative sense. Both agonists and antagonists share common structural features. Composition and arrangement of chemical functional groups, determines the type of pharmacologic effect it possesses. 22-04-2016 16

17. Chemical compound Lead molecule screening SAR studies pruning Pharmacophore 22-04-2016 17

18. Screening Screening is the systematic examination of a chemical molecule to identify the lead molecule. Methods of screening: 1. Identification by Random screening. 2. Identification by Non-Random screening. 3. Identification by drug metabolism studies. 4. Identification by observing side effects. 22-04-2016 18

19. Random Screening The lead compound for the development of most drugs is found by screening thousands of compounds randomly A random screen is a search for a pharmacologically active lead compound without any information about what structures might show activity 22-04-2016 19

20. Identification by drug metabolism studies: azo reductase Prontosil Sulphanilamide 22-04-2016 20

21. Identification by observing side effects: Benzodioxanes Ethanolamines Ethylenediamine Promethazine Chlorpromazine 22-04-2016 21

22. Pruning: Pruning is the refinement of lead structure. It is done to determine the pharmacophore. Pharmacophore: A pharmacophore is a spatial arrangement of functional groups essential for biological activity. It is a pattern that emerges from a set of molecules with a common biological activity. 22-04-2016 22

23. A C D E Benzomorphan Meperidine Morphine Levorphanol B A B D C A D A D B 22-04-2016 23

24. PHYSICOCHEMICAL PROPERTIES OF DRUGS: Acid-Base Properties Water Solubility of Drugs Stereochemistry Electronic parameters 22-04-2016 24

25. Acid-Base Properties Possible to predict ,if a molecule gets  ionized or unionized at a given pH simply by knowing if the functional groups on the molecule are acidic or basic. Quantitatively predict the degree of ionization of a molecule. Henderson- Hassalbach equation 22-04-2016 25

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27. Water Solubility of Drugs It Greatly affects the routes of administration. Two key concepts : 1) hydrogen bond forming( Drugs with possibility of more hydrogen bond formation will have more solubility ) 2) ionization of functional groups. 22-04-2016 27

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29. Predicting Water Solubility: Empiric Approach Based on carbon- solubilising potential of several organic functional groups. Solubilising potential of the functional groups exceeds the total number of carbon atoms present, then the molecule is considered to be water soluble. Otherwise, its water insoluble. 22-04-2016 29

30. Functional groups that can interact either through intramolecular hydrogen or ion-ion interactions will decrease the solubilizing potential of each group. 22-04-2016 30

31. Predicting Water Solubility: Analytical Approach PARTITION CO-EFFICIENT- It is the extent of distribution of drug between oil phase and water phase. If the drug is more hydrophobic it will have high p value and it can cross biological membranes easily. Partition co- effecient of a drug can be determined by its distribution in an octanol -water mixture. P = Concentration of drug in octanol Concentration of drug in aqueous solution 22-04-2016 31

32. Log P = Σπ (fragments) Log of the partition coefficient for a molecule  Predicts Water Solubility Log P is the sum of the hydrophobic and hydriophilic characteristics of the organic functional groups making up the structure of the molecule. Thus, logP is a measure of the solubility characteristics of the entire molecule. 22-04-2016 32

33. MEDC 603 Fall 2007 33 Principles of Drug Design Lipinski’s Rule of Fives MW < 500 Fewer than five H-bond donating functions Fewer than 10 H-bond accepting functions Calculated logP ( ClogP ) between –1 and +5 H 2 O n-octanol P = [D] Lipid [D] Water log P GI Tract Vasculature (after absorption)

34. STEREOCHEMISTRY AND DRUG ACTION Stereo isomers are compounds containing the same number and kinds of atoms, the same arrangement of bonds, but different three-dimensional structures. 2 types  enantiomers and diastereoisomers If functional groups are in the proper 3D orientation, the drug can produce a very strong interaction with its receptor. 22-04-2016 34

35. STEREOCHEMISTRY AND DRUG ACTION 22-04-2016 35

36. The physiochemical properties of a drug molecule dependent on (a) functional groups in the molecule (b)spatial arrangement of these groups. Enantiomers when introduced into an Asymmetric environment(human body) ,it will display different physiochemical properties, producing significant differences in their pharmacokinetic and pharmacodynamics behavior. 22-04-2016 36

37. Easson and Stedman Hypothesis reasoned that differences in biological activity between enantiomers resulted from selective reactivity of one enantiomer with its receptor. They postulated that such interactions require a minimum of a three-point fit to the receptor. ( incerase potency of enantiomers ) 22-04-2016 37

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39. Conformational Isomerism and Biological Activity dynamic process Isomerization takes place via rotation about one or more single bonds. Neurotransmitter acetylcholine  demonstrates the concept of conformational isomers. 22-04-2016 39

40. Rotation around the central C α -C β bond produces the greatest spatial rearrangement of atoms. When the ester and trimethylammonium group are 180° apart, the molecule is said to be in the anti or staggered conformation . maximum separation of the functional groups  most stable 22-04-2016 40

41. Rotation of one end of the C α -C β bond by 120° or 240° results in the two gauche , or skew conformations. Gauche conformation is the form that binds to the nicotinic receptor Anti form, ( achiral ) binds to the muscarinic receptor. 22-04-2016 41

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43. Electronic parameters The electronic effects of various substituents will clearly have an effect on a drug's ionization or polarity. This in turn may have an effect on how easily a drug can pass through cell membranes or how strongly it can bind to a receptor. After drug reaching its target site distribution of electrons in its structure will control the type of bond between them. 22-04-2016 43

44. These SAR studies are done through Analog Approach. ANALOG APPROACH: 1. Homologs. 2. Molecular fragmentation. 3. Addition of functional groups. 4. Isosteric Replacements. 5. Stereochemistry. 6. Ionisation . 22-04-2016 44

45. MOLECULAR FRAGMENTATION: H cocaine tropococaine 22-04-2016 45

46. ADDITION OF FUNCTIONAL GROUPS: Tolazoline Naphazoline 22-04-2016 46

47. ISOSTERIC REPLACEMENTS: 1. Uracil 5-Fluorouracil 2. Hypoxanthine 6-mercaptopurine 22-04-2016 47

48. STEREOCHEMISTRY: Pentobarbitol Amobarbitol tuberculostatic causes blindness Ethambutol 1. 2. 22-04-2016 48

49. O H O H S + Dimethylsulfonium analog Permanently uncharged sulphide I - IONISATION: 22-04-2016 49

50. 50 Camptothecin (CPT) WALL & WANI in early Sixties Camptotheca cuminata,Tree of Joy Quinolino alkaloid Pentacyclic ring structure 22-04-2016

51. 51 STRUCTURE OF CPT WITH IUPAC NAME 22-04-2016

52. 52 A B C D E Saturation of ring B < activity necessary for activity essential for activity, S N inactive D -ring pyridone is required for anti tumor activity. Modifications in rings A , B are well tolerated The stereochemistry at C-20 is very crucial as 20(S) hydroxyl is active, 20(R) inactive modifications at the C , D rings led to complete loss of cytotoxicity. 22-04-2016

53. 53 Modification in rings A,B Topotecan Irinotecan 22-04-2016

54. 54 Modification in rings C,D In general, modifications at the C and D rings of camptothecin led to complete loss of cytotoxicity. If we see these rings, the only positions available for modifications are C-5 , C-14 and C-17 . Several derivatives have been reported either with less activity or with loss of activity. 22-04-2016

55. 55 Modification in ring E The α - hydroxyl lactone system of ring E has been found to be important for the inhibition of the topoisomerase enzyme as well as for in vivo potency Derivatives having a lactam group instead of a lactone , were devoid of topoisomerase inhibitor activity. 22-04-2016

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57. Molecular Modification to Improve the Therapeutic Properties of Cocaine local anesthetic, but bad effect on the central nervous system retains the local anesthetic property 22-04-2016 57

58. Anesthetics Obtained through Molecular Modification 22-04-2016 58

59. Replacing the ester linkage of procaine with an amide linkage led to procainamide hydrochloride Active as a cardiac depressant Active as a local anesthetic Used clinically as an antiarrhythmic 22-04-2016 59

60. Molecular Modification of Morphine Morphine and all the compounds prepared by molecular modification of morphine have a structural feature in common 22-04-2016 60

61. Molecular Modification of Codeine Dextromethorphan is the major ingredient in most cough medicines 22-04-2016 61

62. The tranquilizer Librium was discovered accidentally 22-04-2016 62

63. Structural modification of Librium leads to the generation of other tranquilizers 22-04-2016 63

64. Many drugs exert their physiological effects by binding to a specific cellular binding site called a receptor Excess histamine in the body causes the symptoms associated with the common cold and allergic responses 22-04-2016 64

65. Antihistamines alleviate the action of histamine by binding to the histamine receptor 22-04-2016 65

66. 4-Methylhistamine is used as a lead compound to develop antiulcer drugs 22-04-2016 66

67. In screening modified compounds, it is possible to find a compound with completely different pharmacological activity than the lead compound e.g.  in 1942 by the chemist Marcel Janbon et al. an antibiotic a drug with hypoglycemic activity 22-04-2016 67

68. Molecular modification of promethazine leads to the discovery of an antipsychotic drug 22-04-2016 68

69. Drugs as Enzyme Inhibitors Penicillin destroys bacteria by inhibiting the enzyme that synthesizes bacterial cell walls 22-04-2016 69

70. Antiviral Drugs These nucleoside analogs interfere with DNA or RNA synthesis 22-04-2016 70

71. - Quantitative structure-activity relationships are mathematical relationships linking chemical structure and pharmacological activity in a quantitative manner for a series of compounds - Biological activity can be expressed quantitatively as the concentration of a substance required to give a certain biological response - When physicochemical properties or structures are expressed by numbers, one can find a mathematical relationship, or quantitative structure-activity relationship, between the two QSAR 4/22/2016 71

72. Conclusion : SAR deals with the influence of the functional groups present in the drug on its biological activity SAR studies are done to determine the pattern of this influence which is employed in the drug design and in the synthesis of many drugs of desired pharmacological activity. 22-04-2016 72

73. References: Medicinal Chemistry, Ashutosh Kar , 4 th edi . Essentials of drug designing . V kothekar 1 st Edition 2005 Paul Beringer , Linda Felton et al. The Science and Practice of Pharmacy, 21 st ed , Vol.1, Drug design vol.10, Ariens et al. Goodman & gillman’s the pharmacological basis of therapeutics, 12 th edition. 22-04-2016 73