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Drug Design: Functional groups / Pharmacological Activity

Drug Design: Functional groups / Pharmacological Activity. Structure - Mechanism of action (Interaction with target). Structure - Physiochemical properties (Bioavailability etc) Acid / base properties Water solubility Partition coefficient (Crystal structure)

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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 (Interaction with target) • Structure - Physiochemical properties (Bioavailability etc) • Acid / base properties • Water solubility • Partition coefficient • (Crystal structure) • Stereochemistry ADME Absorbtion. Distribution, Metabolism, Excretion (ADMET, ADMEtox) KJM5230-H06

  2. Structure - Mechanism of action KJM5230-H06

  3. Structure - Mechanism of action SAR: Structure Activity Relationships Acetylcholine agonists: Small N-quartenary compds. Acetylcholine antagonists: Larger N-quartenary compds. KJM5230-H06

  4. Active compound identified Target? Target identified Ligand? KJM5230-H06

  5. 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-H06

  6. Cyclopentolate - tertiary amine, pKa ca. 10 pH=pKa; [acid]= [base] pH<pKa; acid form dominates pH>pKa; basic form dominates = active form KJM5230-H06

  7. Antibacterial sulfonamides Old compound Modern compound base form, ionic, water sol. KJM5230-H06

  8. 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-H06

  9. The more H-bonds possible - the more water sol. KJM5230-H06

  10. 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-H06

  11. Water solubilization of functional groups Ex. polyfunctional comp. Charge: 1 charge - 20-30 C KJM5230-H06

  12. Structure - Physiochemical properties • Acid / base properties • Water solubility • Partition coefficient • (Crystal structure) • Stereochemistry logP P: Partition coefficient between n-octanol and water Experimental: MlogP or logPmeas logP  Rt (HPLC, TLC reverse phease) Calcd: ClogP p-value: hydrophilic - lipophilic value ClogP (SciFinder): 2.69 KJM5230-H06

  13. Absorbtion of Bioactive Compounds Absorbtion from GI tract KJM5230-H06

  14. Most drugs: Passive diffusion Low lipophilicity unionized form - low absorbtion logP - P: Partition coefficient between n-octanol and water KJM5230-H06

  15. Crossing the membrane Passive transport / diffusion Rate  Conc. absortion site (1. order kinetics) % Drug absorbed  lipophilicity Size of molecule Certain ionic compounds may go thru as ion-pair KJM5230-H06

  16. Active transport / Carrier mediated transport • Less common • Structural recemblanse with for instance nutritional compound • Transport against conc. gradient • Mechanism saturated at high conc. • Competition for carrier molecules, compounds with structural resemblance KJM5230-H06

  17. The Lipinski "Rule of Five" states that compounds are likely to have good absorption and permeation in biological systems and are more likely to be successful drug candidates if they meet the following criteria: five or fewer hydrogen-bond donors ten (2 x 5) or fewer hydrogen-bond acceptors molecular weight less than or equal to 500 calculated logP less than or equal to 5 *Compound classes that are substrates for biological transporters are exceptions to the rule. Not too polar Not too big Not too hydrophobic KJM5230-H06

  18. Structure - Physiochemical properties • Acid / base properties • Water solubility • Partition coefficient • (Crystal structure) • Stereochemistry 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

  19. Restricted rotation - optically active rotamers KJM5230-H06

  20. 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-H06

  21. Antimycobacterials KJM5230-H06

  22. 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-H06

  23. 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-H06

  24. Non-classical bioisosters • Not strong steric or electronic similarities KJM5230-H06

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