DOCK 4.0: Search strategies for automated molecular docking of flexible molecule databases

In this paper we describe the search strategies developed for docking flexi ble molecules to macomolecular sites that are incorporated into the widely distributed DOCK software, version 4.0. The search strategies include incre mental construction and random conformation search and utilize the existing Coulombic and Lennard-Jones grid-based scoring function. The incremental c onstruction strategy is tested with a panel of 15 crystallographic testcase s, created from 12 unique complexes whose ligands vary in size and flexibil ity. For all testcases, at least one docked position is generated within 2 Angstrom of the crystallographic position. For 7 of 15 testcases, the top s coring position is also within 2 Angstrom of the crystallographic position. The algorithm is fast enough to successfully dock a few testcases within s econds and most within 100 s. The incremental construction and the random s earch strategy are evaluated as database docking techniques with a database of 51 molecules docked to two of the crystallographic testcases. Increment al construction outperforms random search and is fast enough to reliably ra nk the database of compounds within 15 s per molecule on an SGI R10000 cpu.