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Drug Design: Functional groups / Pharmacological Activity

Drug Design: Functional groups / Pharmacological Activity. Structure  Mechanism of action. Structure  Physiochemical properties Acid / base properties Water solubility Partition coefficient Crystal structure Stereochemistry. ADME.

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Drug Design: Functional groups / Pharmacological Activity

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  1. Drug Design: Functional groups / Pharmacological Activity Structure  Mechanism of action • Structure  Physiochemical properties • Acid / base properties • Water solubility • Partition coefficient • Crystal structure • Stereochemistry ADME Absorbtion. Distribution, Metabolism, Excretion (ADMET, ADMEtox) KJM5230-H04

  2. Structure  Mechanism of action KJM5230-H04

  3. Structure  Mechanism of action SAR: Structure Activity Relationships Acetylcholine agonists: Small N-quartenary compds. Acetylcholine antagonists: Larger N-quartenary compds. KJM5230-H04

  4. Structure  Physiochemical properties • Acid / base properties • Water solubility • Partition coefficient • Crystal structure • Stereochemistry Human body: ca 75% water pH blood ca 7.4 (physiolog. pH) pH stomach 1 - 3.5 pH duodenum ca. 4 pH urine ca. 6 Identification of acidic / basic functional groups pKa determines degree of ionization different places in the body KJM5230-H04

  5. Cyclopentolate - tertiary amine, pKa ca. 10 pH=pKa; [acid]= [base] pH<pKa; acid form dominates pH>pKa; basic form dominates = active form KJM5230-H04

  6. Antibacterial sulfonamides Old compound Modern compound base form, ionic, water sol. KJM5230-H04

  7. Structure  Physiochemical properties • Acid / base properties • Water solubility • Partition coefficient • Crystal structure • Stereochemistry Ionisation -permanent charge -acid / base properties Hydrogen bonds Salts between weak organic acids and weak organic bases does not dissolve well in water KJM5230-H04

  8. The more H-bonds possible - the more water sol. KJM5230-H04

  9. Prediction of water solubility - Empirical Water solubilization of functional groups Ex. monofuctional comp. methanol - pentanol/hexanol are solubile (solubile: >10 mg/mL) Charge: 1 charge - 20-30 C KJM5230-H04

  10. Water solubilization of functional groups Ex. polyfunctional comp. Charge: 1 charge - 20-30 C KJM5230-H04

  11. Prediction of water solubility - Analytical logP P: Partition coefficient between n-octanol and water Experimental: MlogP or logPmeas Calcd: ClogP logP  Rt (HPLC, TLC reverse phease) p-value: hydrophilic - lipophilic value ClogP (SciFinder): 2.69 KJM5230-H04

  12. Structure  Physiochemical properties • Acid / base properties • Water solubility • Partition coefficient • Crystal structure • Stereochemistry cis-trans Diastereomers Enantiomers (Konformers / rotamers) KJM5230-H04

  13. Biomolecules (reseptors, enzymes): Asymmetric • Enantiomers may behave differently: • Absorbtion (membrane selectivity) • Metabolism • Binding to other reseptors than target • (loss, side effects) • Binding to target reseptor KJM5230-H04

  14. Restricted rotation - optically active rotamers KJM5230-H04

  15. Screening/Design/Serendipity/Natural products • Lead compound • Structure Optimisation • Actual Drug • Refinement of lead structure: • Determining pharmacophore • Functional group modification Pharmacophore: The part of the molecule that contains the functional groups that actually binds to the reseptor KJM5230-H04

  16. Antimycobacterials KJM5230-H04

  17. Improvement of lead by functional group modification • Activity • Toxicity • Bioavailability • Metabolism Isosters: Functional groups that results in approx. the same properties Steric and electronic similarities KJM5230-H04

  18. Bioisosters: Functional groups that results in approx. the same biological properties • Classical bioisosters • Steric and electronic similarities Tetravalente Monovalent -F, -H -OH, -NH2 -H, -F, -OH, -NH2, -CH3 -SH, -OH -Cl, -Br, -CF3 Divalent -C=S, -C=O, -C=NH, -C=C- Trivalente -CH=, -N= Rings KJM5230-H04

  19. Non-classical bioisosters • Not strong steric or electronic similarities KJM5230-H04

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