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

https://doi.org/10.1016/S0022-2836(95)80037-9Get rights and content

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.

References (41)

  • BeesonC et al.

    A comprehensive description of the free energy of an intramolecular hydrogen-bond as a function of solvation: NMR study

    J. Amer. Chem. Soc.

    (1993)
  • BlaneyJ.M. et al.

    A good ligand is hard to find: automated docking methods

    Perspect. Drug Disc. Design.

    (1993)
  • BlommersM.J. et al.

    Conformational analysis of a dinucleotide photodimer with the aid of a genetic algorithm

    Biopolymers

    (1992)
  • BrownR.D. et al.

    Matching two-dimensional chemical graphs using genetic algorithms

    J. Chem. Inform. Commit. Sci.

    (1994)
  • CheungH.T.A. et al.

    13C NMR determination of the tautomeric and ionization states of folate in its complexes with Lactobacillus cnsei dihydrofolate reductase

    Biochemistry

    (1993)
  • ClarkD.E. et al.

    Pharmacophoric pattern matching in files of three-dimensional chemical structures: comparison of conformational-searching algorithms for flexible searching

    J. Chem. Inform. Comput. Sci.

    (1994)
  • ClarkM. et al.

    Validation of the general-purpose TRIPOS 5.2 force field

    J. Comput. Chem.

    (1989)
  • CramerC.J. et al.

    Quantum Chemical Program Exchange

  • DandekarT. et al.

    Folding the main chain of small proteins with the genetic algorithm

    J. Mol. Biol.

    (1993)
  • DavisJ.F. et al.

    Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate

    Biochemistry

    (1990)
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