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Pharmacophore Based Drug Design
Pharmacophore Based Drug Design
B: Etc…
Example 2 (cont):
Notes:
•More rigid molecules have fewer conformations – easier to analyze
•Flexible molecules have many conformations – often must examine
conformationally restricted analogs to determine bioactive
conformation. (Move from computer to lab: Chemical synthesis of
analogs!) (Ex. GABA MC C2.5.2)
•Superimposing molecules: don’t look at sterics only – think of
physical properties of molecule.
Pharmacophore-Based Drug Design
1. Chemical modification
2. Database searching
3. De novo
4. Manual
O N no activity
OH
H
no activity ?
N HN N
Propranolol (beta blocker) H H
OH OH
no activity active
(but less than
Propranolol)
Pharmacophore-based drug design
Design method 1: Chemical modification
Pharmacophore-based drug design
Design method 1: Chemical modification
O N O N
H H
OH OH
N
H
Propranolol (beta blocker) Pindolol
potent very potent
Pharmacophore-based drug design
Design method 1: Chemical modification
Pharmacophore-based drug design
Design method 1: Chemical modification
Convert to:
•methyl ether (no H-bond donor now; maybe steric problem)
•an ester (no H-bond donor now; poor H-bond acceptor; maybe steric
problem)
Probing specific functional groups in a molecule
Binding role of hydroxy groups (continued):
methyl ether (no H-bond donor now; still H-bond acceptor; maybe
steric problem)
an ester (no H-bond donor now; poor H-bond acceptor; maybe steric
problem)
Probing specific functional groups in a molecule
CH3 H O O
DRUG N DRUG N DRUG
R R NR2
Probing specific functional groups in a molecule
Notes:
•Recall impact of lipophilicity on drug transport through body
•Changing alkyl groups may also affect the preferred
conformation of the molecule!
Probing specific functional groups in a molecule
MeSO2NH O
6
7 O
NR
8
Anti-arhythmic benzopyran
Best when substituent was at position 7
Probing specific functional groups in a molecule
Binding role of aryl substituents: (continued)
Example: beta-adrenergic drugs, chemically related to
adrenaline and noradrenaline.
Probing specific functional groups in a molecule
Binding role of amides: H-bond acceptor; dipole-dipole
Convert to:
•Hydrolysis products (but will lose a piece); reduce (no more H-bond
acceptor
Pharmacophore-based drug design
Design method 1: Chemical modification
Other “hits”
References
Patrick, G. L. An Introduction to Medicinal Chemistry; Oxford University Press: New York, NY, 2001
Silverman, R. B. The Organic Chemistry of Drug Design and Drug Action ; Academic Press: San Diego,
CA, 1992.
Thomas, G. Medicinal Chemistry An Introduction; John Wiley and Sons, Ltd.: New York, NY, 2000.
Williams, D. A.; Lemke, T. L. Foye’s Principles of Medicinal Chemistry; Lippincott Williams and Wilkins,
New York, NY, 2002.