Full Toolbox Required to Compete Successfully

1
Rational Drug Discovery

• Full Toolbox Required to Compete Successfully

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)

3
Receptor-based Drug Design

• Design of Antithrombin Activators

4
Receptor-based Drug Design

• Binding Site Information

Arg47
Lys114
Lys125
Arg46
Arg129
Asn45
Arg13
Lys11
5
Receptor-based Drug Design

• Thermodynamics

-DGO (kcal/mol)
6
Receptor-based Drug Design

• Computerized Modeling

7
Receptor-based Drug Design

• Design of New Structures

8
Pharmacophore-based Drug Design

• Natural Product Derivatization and Pharmacophore
  Elucidation

9
Mechanism-based Drug Design

• Design of HIV Protease Inhibitor

Mechanism of Aspartic Proteinases
10
Mechanism-based Drug Design
IC50 (nM)
Inhibitor Structure
HIV-1 HIV-2
Z.Phe?CH(OH)CH2NPro.OtBu
6,500
Z.Asn.Phe?CH(OH)CH2NPro.OtBu 140
330
Z.Asn.Phe?CH(OH)CH2NPro.OtBu 300

11
Rational Design of HIV-1/2 Proteinase Inhibitors
IC50 (nM)
Inhibitor Structure
HIV-1 HIV-2
Z.Leu.Asn.Phe?CH(OH)CH2NPro.Ile.NHiBu 750

Z.Asn.Phe?CH(OH)CH2NPro.NHiBu
210
Z.Asn.Phe?CH(OH)CH2NPIC.NHiBu
18
12
Rational Design of HIV-1/2 Proteinase Inhibitors
IC50 (nM)
Inhibitor Structure
HIV-1 HIV-2
QC.Asn.Phe?CH(OH)CH2NPIC.NHiBu 2
9.5
QC.Asn.Phe?CH(OH)CH2NDIQ.NHiBu lt0.4
lt0.8