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Structure activity relationship in drug action


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Structure activity relationship in drug action

  1. 1. Structure activity relationship in drug action Presented by- Dr Suyash Bharat PG JR 1ST PHARMACOLOGY, GMC Haldwani (Nanital)
  2. 2. Structure activity relationship (SAR). • 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.
  3. 3. • SAR is the relationship between the chemical or 3D structure of a molecule and its biological activity. • 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)
  4. 4. 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.
  5. 5. History- Brown and Fraser in 1869 • They showed that many compounds containing tertiary amine groups became muscle relaxants when converted to quaternary ammonium compounds. • This hypothesis was later rejected. • Ing states “Molecules that block the effects of natural neurotransmitters (antagonists) generally are larger in size than the native compound.”
  6. 6. • Both agonists and antagonists share common structural features. • Composition and arrangement of chemical functional groups, determines the type of pharmacologic effect ,it possesses.
  7. 7. Selectivity of Drug Action and Drug Receptors • Similar molecules exert similar biological actions in a qualitative sense.
  8. 8. PHYSICOCHEMICAL PROPERTIES OF DRUGS: • Acid-Base Properties • Water Solubility of Drugs • STEREOCHEMISTRY • Electronic parameters
  9. 9. 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
  10. 10. 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.
  11. 11. R O H Alchohol O HH H O H O H H 3 H-Bonds OAldehyde / ketone HH O H O H 2 H-Bonds R R' OEster HH O H O H 3 H-Bonds R O R H O H Ion - dipole bonds H N HR H Acidic form of amines H O H - + + R O O Basic form of carboxylic acid (carboxylate) H O H + + -
  12. 12. 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.
  13. 13. • Functional groups that can interact either through intramolecular hydrogen or ion-ion interactions will decrease the solubilizing potential of each group. Intramoleculare interact. reduce water sol. R CO2 NH3 Strong intramolec interact. O H H O HH
  14. 14. 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
  15. 15. 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 themolecule. • Thus, logP is a measure of the solubility characteristics of the entire molecule.
  16. 16. 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.
  18. 18. • 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 pharmacodynamic behavior.
  19. 19. 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)
  20. 20. 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.
  21. 21. • Rotation around the central Cα-Cβ 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. 22. • Rotation of one end of the Cα-Cβ 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.
  23. 23. Chemical compound screening Lead molecule pruning(refinement of lead structure) Pharmacophore (its a spatial arrangement of functional groups essential for biological activity)
  24. 24. Determination of the Pharmacophore • The pharmacophore of a drug molecule is that portion of the molecule containing the essential organic functional groups that directly interact with the receptor active site • Pharmacophore may constitute a small portion of the molecule.(very specific) • Example narcotic analgesic morphine.
  25. 25. Alterations in Alkyl Chains: Chain Length, Branching, and Rings • Simply changing the length of an alkyl chain by one CH2 unit or branching the chain may alter its lipophilic character properties of absorption, distribution, and excretion alter. • Alkyl chain is directly involved in the receptor interaction alter the binding characteristics. • Conformational become less flexible affect spatial relationship of functional groups influence receptor binding
  26. 26. FUNCTIONAL GROUP MODIFICATION. ISOSTERISM AND BIOISOSTERISM • Modify the compound to reduce or eliminate undesirable features without losing the desired biological activity. • Done by Replacement or modification of functional groups with other groups having similar properties is known as "isosteric replacement" or "bioisosteric replacement"
  27. 27. Langmuir in 1919 defined the concept of isosterism: • "Comolecules are thus isosteric if they contain the same number and arrangement of electrons. The comolecules of isosteres must, therefore, contain the same number of atoms. The essential differences between isosteres are confined to the charges on the nuclei of the constituent atoms."
  28. 28. • Describe the similarities in physical properties among atoms, functional groups, radicals, and molecules.
  29. 29. • Hinsberg applied the concept of isomerism to entire molecules  developed the concept of "ring equivalents” • The groups that can be exchanged for one another in aromatic ring systems without drastic changes in physicochemical properties relative to the parent structure. • Eg -Benzene, thiophene, and pyridine
  30. 30. • "Bioisostercs are compounds or groups that possess near equal molecular shapes and volumes, approximately the same distribution of electrons, and which exhibit similar physical properties such as hydrophobicity. • Bioisosteric compounds affect the same biochemically associated systems as agonist or antagonists and thereby produce biological properties that are related to each other."
  31. 31. α- tocopherol
  32. 32. • Nonclassical bioisosteres are replacements of functional groups not defined by classical definitions. • Thou they mimic spatial arrangements , electronic properties, or some other physiochemical property of the molecule or functional group critical for biological activity.
  33. 33. • eg -use of a double bond to position essential functional groups into a particular spatial configuration critical for activity. • The trans isomer of diethylstilbestrol has approximately the same potency as estradiol, whereas the cis isomer is only one-fourteenth as active.
  34. 34. FUNCTIONAL GROUP MODIFICATION. Scaffold Hopping • Bioisosterism include the replacement of the initial molecular scaffold by a different one, keeping the same biological activity called scaffold hopping. • Eg- diazepam, zolpidem, zaleplon , and zopiclone which exert the same biological response acting as full agonists of GABA-A (g-aminobutyric acid) receptor at the benzodiazepine site though being structurally different.
  35. 35. • Examples illustrated that similar biological activity can be obtained with structurally different molecules which seems to contradict the bioisosterism principle discussed.
  36. 36. Electronic parameters • Charge – sum of partial charge • F charge- sum of formal charge • Apol -sum of atomic polarizability • Dipole – dipole movement • HOMO-highest occupied molecular orbital energy • LUMO- lowest unoccupied molecular orbital energy • Sr – superdelocalizability.
  37. 37. References • Medicinal Chemistry I -IInd Module, Drug design. • Essentials of drug designing . V kothekar 1st Edition 2005 • SAR applicability domain -Nina Nikolova and Joanna Jaworska.
  38. 38. Thank you
  39. 39. Technologies used • Structural information obtained from- • 1) X-ray crystallography • 2) nuclear magnetic resonance spectroscopy