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Abstract
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.