Molecular recognition of receptor sites using a genetic algorithm with a description of desolvation

Understanding the principles whereby macromolecular biological receptors can recognise small molecule substrates or inhibitors is the subject of a major effort. This is of paramount importance in rational drug design where the receptor structure is known (the “docking” problem). Current theoretical...

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Bibliographic Details
Published inJournal of molecular biology Vol. 245; no. 1; pp. 43 - 53
Main Authors Jones, Gareth, Willett, Peter, Glen, Robert C.
Format Journal Article
LanguageEnglish
Published England Elsevier Ltd 1995
Subjects
Arabinose - chemistry
Computer Simulation
desolvation
Drug Design
Galactose - chemistry
genetic algorithm
Macromolecular Substances
Models, Genetic
Oxidoreductases - chemistry
Protein Conformation
protein ligand docking
Receptors, Drug - chemistry
genetic algorithm
DHFR
NADPH
NMR
4g-neu5Ac2en
desolvation
GA
r.m.s
protein ligand docking
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Summary:Understanding the principles whereby macromolecular biological receptors can recognise small molecule substrates or inhibitors is the subject of a major effort. This is of paramount importance in rational drug design where the receptor structure is known (the “docking” problem). Current theoretical approaches utilise models of the steric and electrostatic interaction of bound ligands and recently conformational flexibility has been incorporated. We report results based on software using a genetic algorithm that uses an evolutionary strategy in exploring the full conformational flexibility of the ligand with partial flexibility of the protein, and which satisfies the fundamental requirement that the ligand must displace loosely bound water on binding. Results are reported on five test systems showing excellent agreement with experimental data. The design of the algorithm offers insight into the molecular recognition mechanism.
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ISSN:0022-2836
1089-8638
DOI:10.1016/S0022-2836(95)80037-9