Inhibitor Design, Based on Protein Structure

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Inhibitor Design, Based on Protein Structure

• Supa Hannongbua
• Department of Chemistry, Faculty of Science,
• Kasetsart University, Bangkok, Thailand
• e-mail fscisph_at_ku.ac.th
• http//kuchem.sci.ku.ac.th

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Outline
Outline

• Impact of Computer-Assisted Drug Design (CADD)
• Inhibitor Design, Based on Protein Structure
  

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How are drugs discovered ?
By serendipity (Chlordiazepoxyde, Aspartam,
etc...) by structure-activity relationships
(most) from natural products (digitalin,
taxol) by rational design (since the 80s) by
systematic screening (since the 90s)
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Impact of Computer-Assisted Drug Design (CADD)
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Annual turnover of leading pharmaceutical
companies (in millons US- )
Glaxo 8.88x109 Merck 8.53x109 Bristol-
M. 7.70x109 Amer. Home Products 7.67x109 Pf
izer 6.38x109 SmithKline Beecham 6.35x109
Johnson Johnson 6.25x109
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Annual turnover of most important drugs (in
millions US- )
Zantac (Glaxo) 4.01x109 Renitec
(Merck) 2.04x109 Prozac (Lilly) 1.58x109
Zovirax (Wellcome) 1.53x109 Zocor
(Merck) 1.37x109 Augmentin
(S.K.Beecham) 1.32x109 Voltaren
(Ciba) 1.26x109
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Pharmaceutical Industry
1994 2.50x1011 US
Glaxo Wellcome Ciba Sandoz Novartis
Research Investment Glaxo Wellcome
1.9x109 US
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Pharmaceutical research topics

• New products with enhanced activity

• New products with diminished side effects

• Need of new products caused by increasing
  resistance

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Number of new chemical entities on the market
1960-1969 70-100 1970-1979 60-70 1980-1989
50 1990-1994 35-45
Increasing development costs by additional legal
requirements
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Development of New Drugs
Higher efficiency
Diminished side effects
New products
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High development costs
Unfavourable ratio between synthesized compounds
and products on the market
Expensive test procedure
Preclinical Clinical test (phase
I-III)
Market support
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Product Development

• Selection of a leading compound

• Development of synthetic procedures

• Development of a proper testing system

• Synthetic screening

• Preclinical Tests

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Synthetic screening starting from
known drugs physiological compounds natural
products
Synthesized Compounds 1000 1
Development Compound   Development Compound
10 1 Registered Drug
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Clinical Tests
Phase 1 Tests on healthy males Pharmacokinetics,
pharmacodynamics, Toxicity
Phase 2 Tests on a limited number of persons
with specific disease Efficacy
Phase 3 Global tests on broad clinical
basis Definite safety, optimal dosage schedule
Phase 4 Registration, Market Support
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Support by Molecular Modeling

• Modeling of the ligand molecules

• Conformational analysis of the ligand

• Calculation of the electronic properties of the
  ligand

• Estimation of the pharmacophor

• Generation of new compounds

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Ligand Docking Simulation of the association
complexation De novo Design
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Experimental Support
X-ray crystallography (of proteins and
protein-ligand complexes)
NMR spectroscopy (proteins in solution)
Isolation of the enzyme
Purification of the enzyme
Crystallization of the enzyme
Preparation of the enzyme-ligand complex
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Computer-Assisted Drug Design
Case 1 Structure of the Receptor is not known
(Analog-based Drug Design) Case
2 Structure of the Receptor is known
(Inhibitor Design, Based on Protein
Structure) Case 3 Structure of the Receptor is
not known and no quantitative information about
the biological effect is available