Docking of small ligands to low‐resolution and theoretically predicted receptor structures

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Abstract
We have developed a simple docking procedure that is able to utilize low-resolution models of proteins created by structure prediction algorithms such as threading or ab initio folding to predict the conformation of receptor–small ligand complexes. In our approach, using only approximate, discretized models of both molecules, we search for the steric and quasi-chemical complementarity between a ligand and the receptor molecules. This averaging procedure allows for the compensation of numerous structural inaccuracies resulting from the theoretical predictions of the receptor structure. The best relative orientation of these two models is obtained by an exhaustive scan over the rigid body's six-dimensional translational and rotational degrees of freedom. The search method is based on a real space grid-searching algorithm, unlike docking methods based on the fast Fourier Transform algorithm. We have applied this algorithm to rebuild structures of several complexes available in the Protein Data Bank. The structures of the receptors are produced by means of our threading algorithm PROSPECTOR, subsequently refined, and then utilized in the docking experiment. In many cases, not only is the localization of the binding site on the receptor surface correctly identified, but the proper orientation of the bounded ligand is also reasonably well reproduced within the level of accuracy of the modeled receptor itself. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 189–197, 2002