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.