1. Rational Drug Discovery
Full Toolbox Required to Compete Successfully
Biological
Discovery
High Volume
Screening
Combinatorial
Diversity
Rational
[Structure, Design,
Informatics]
Lead Discovery
Research
Biodisposition
Toxicity
Efficacy
Pharmacokinetics
Preclinical
R&D
IND
Lead Series
Iterative
Process
MEDC 607 & MEDC 603

2. Rational Drug Discovery
Definition
Rational – Reason-based
Not based on chance alone
May not involve computers
Types of Drug Discovery Searches
Structure – based Drug Design
(structure of the receptor, binding site, AA residues, thermodynamics)
Pharmacophore – based Drug Design
(structure of the ligand, SAR, QSAR)
Mechanism – based Drug Design
(molecular mechanism of action, transition state)
MEDC 607 & MEDC 603

3. Receptor-based Drug Design
Design of Antithrombin Activators
MEDC 607 & MEDC 603

4. Receptor-based Drug Design
Binding Site Information
Lys114
Arg47
Lys125
Arg129
Arg46 _
Asn45
Arg13
Lys11
MEDC 607 & MEDC 603

5. Receptor-based Drug Design
Thermodynamics
-DGO (kcal/mol)
MEDC 607 & MEDC 603

6. Receptor-based Drug Design
Computerized Modeling
MEDC 607 & MEDC 603

7. Receptor-based Drug Design
Design of New Structures
A) B)
ECS = (2S,3S)
(+)CS = (2S,3R)
MoS :: R = H, R’ = OSO3-
QS :: R = OSO3-, R’ = H 2 3
Pentasaccharide Binding Site Residues
HINT Score
DEF =
ECS =
MEDC 607 & MEDC 603

8. Pharmacophore-based Drug Design
Natural Product Derivatization and Pharmacophore Elucidation
Morphine R = R’ = H
Codeine R = Me, R’ = H
Heroin R = R’ = COCH3
(Analgesic + additive)
Levorphanol
(a morphinan)
(3 – 4X morphine analgesic
+ retains additive property)
Pentazocine
(less potent than morphine
+ reduced additive property)
Methadone
(equipotent as morphine analgesic
+ almost no additive)
Meperidine
(10-12% of morphine analgesic
+ much lowered additive)
(less potent than morphine
+ reduced additive property)
MEDC 607 & MEDC 603

9. Mechanism of Aspartic Proteinases
Mechanism-based Drug Design
Design of HIV Protease Inhibitor _ _ + _ _
Mechanism of Aspartic Proteinases _ _ _
MEDC 607 & MEDC 603

10. Mechanism-based Drug Design
IC50 (nM)
Inhibitor Structure HIV HIV-2
Z.Phe[CH(OH)CH2N]Pro.OtBu ,500
Z.Asn.Phe[CH(OH)CH2N]Pro.OtBu
Z.Asn.Phe[CH(OH)CH2N]Pro.OtBu
MEDC 607 & MEDC 603

11. Rational Design of HIV-1/2 Proteinase Inhibitors
IC50 (nM)
Inhibitor Structure HIV HIV-2
Z.Leu.Asn.Phe[CH(OH)CH2N]Pro.Ile.NHiBu
Z.Asn.Phe[CH(OH)CH2N]Pro.NHiBu
Z.Asn.Phe[CH(OH)CH2N]PIC.NHiBu
MEDC 607 & MEDC 603

12. Rational Design of HIV-1/2 Proteinase Inhibitors
IC50 (nM)
Inhibitor Structure HIV HIV-2
QC.Asn.Phe[CH(OH)CH2N]PIC.NHiBu
QC.Asn.Phe[CH(OH)CH2N]DIQ.NHiBu < <0.8
MEDC 607 & MEDC 603