MCDOCK: A Monte Carlo simulation approach to the molecular docking problem

Prediction of the binding mode of a ligand (a drug molecule) to its macromo lecular receptor, or molecular docking, is an important problem in rational drug design. We have developed a new docking method in which a non-convent ional Monte Carlo (MC) simulation technique is employed. A computer program , MCDOCK, was developed to carry out the molecular docking operation automa tically. The current version of the MCDOCK program (version 1.0) allows for the full flexibility of ligands in the docking calculations. The scoring f unction used in MCDOCK is the sum of the interaction energy between the lig and and its receptor, and the conformational energy of the ligand. To valid ate the MCDOCK method, 19 small ligands, the binding modes of which had bee n determined experimentally using X-ray diffraction, were docked into their receptor binding sites. To produce statistically significant results, 20 M CDOCK runs were performed for each protein-ligand complex. It was found tha t a significant percentage of these MCDOCK runs converge to the experimenta lly observed binding mode. The root-mean-square (rms) of all non-hydrogen a toms of the ligand between the predicted and experimental binding modes ran ges from 0.25 to 1.84 Angstrom for these 19 cases. The computational time f or each run on an SGI Indigo2/R10000 varies from less than 1 min to 15 min, depending upon the size and the flexibility of the ligands. Thus MCDOCK ma y be used to predict the precise binding mode of ligands in lead optimizati on and to discover novel lead compounds through structure-based database se arching.