1. 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
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
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 C
KJM5230-H04

10. Water solubilization of functional groups
Ex. polyfunctional comp.
Charge: 1 charge 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. Structure Optimisation
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. Classical bioisosters Steric and electronic similarities
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