A Comparison of Global and Local Search Methods in Drug Docking.

Abstract

Molecular docking software makes computational predictions of the interaction of molecules. This can be useful, for example, in evaluating the binding of candidate drug molecules to a target molecule from a virus. In the Autodock docking software [11], a physical model is used to evaluate the energy of candidate docked con gurations, and heuristic search is used to minimize this energy. Previous versions of Autodock used simulated annealing to do this heuristic search. We evaluate the use of the genetic algorithm with local search inAutodock. We investigate several GA-local search (GA-LS) hybrids and compare results with those obtained from simulated annealing. This comparison is done in terms of optimization success, and absolute success in nding the true physical docked con guration. We use these results to test the energy function and evaluate the success of the application. 1 The Docking Problem When two molecules are in close proximity, it can be energetically favorable for them to bind together tightly. The molecular docking problem is the prediction of energy and physical con guration of binding between two molecules. Atypical application is in drug design, in which we might dock a small molecule that is a proposed drug design to an enzyme we wish to target. For example, HIV protease is an enzyme in the AIDS virus that is essential to its replication. The chemical action of the protease takes place at a localized active site on its surface. HIV protease inhibitor drugs are small molecules that bind to the active site in HIV protease and stay there, so that the normal functioning of the enzyme is prevented. Docking software allows us to evaluate a drug design by predicting whether it will be successful in binding tightly to the active sitein the enzyme. Based on the success of docking, and the resulting docked con guration, designers can re ne the drug molecule. 1.1 Autodock Autodock docks small exible substrate molecules to large rigid macromolecules (such as proteins) [4, 11]. A candi-