LigandFit: a novel method for the shape-directed rapid docking of ligands to protein active sites.
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.
Venkatachalam
C M
CM
Accelrys Inc., 9685 Scranton Road, San Diego, CA 92121, USA. venkat@accelrys.com
Jiang
X
X
Oldfield
T
T
Waldman
M
M
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
D008024:Ligands; D011506:Proteins