title: LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites.
abstract: We present a new shape-based method, LigandFit, for accurately docking ligands into protein active sites. The method employs a cavity detection algorithm for detecting invaginations in the protein as candidate active site regions. A shape comparison filter is combined with a Monte Carlo conformational search for generating ligand poses consistent with the active site shape. Candidate poses are minimized in the context of the active site using a grid-based method for evaluating protein-ligand interaction energies. Errors arising from grid interpolation are dramatically reduced using a new non-linear interpolation scheme. Results are presented for 19 diverse protein-ligand complexes. The method appears quite promising, reproducing the X-ray structure ligand pose within an RMS of 2A in 14 out of the 19 complexes. A high-throughput screening study applied to the thymidine kinase receptor is also presented in which LigandFit, when combined with LigScore, an internally developed scoring function, yields very good hit rates for a ligand pool seeded with known actives.
authors.affiliation: Accelrys Inc., 9685 Scranton Road, San Diego, CA 92121, USA. venkat@accelrys.com
authors.forename: C M
authors.initials: CM
authors.lastname: Venkatachalam
authors.forename: X
authors.initials: X
authors.lastname: Jiang
authors.forename: T
authors.initials: T
authors.lastname: Oldfield
authors.forename: M
authors.initials: M
authors.lastname: Waldman
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D003198:Computer Simulation; D008024:Ligands; D008433:Mathematics; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D012984:Software
chemical_list: D008024:Ligands; D011506:Proteins