Multiple target screening method for robust and accurate in silico ligand screening.
We developed a new in silico multiple target screening (MTS) method, based on a multi-receptor versus multi-ligand docking affinity matrixes, and examined its robustness against changes in the scoring system. According to this method, compounds in a database are docked to multiple proteins. The compounds among these proteins that are likely bind to the target protein are selected as the members of the candidate-hit compound group. Then, the compounds in the group are sorted into descending order using the docking score: the first (n-th) compound is expected to be the most (n-th) probable hit compound. This method was applied to the analysis of a set of 142 receptors and 142 compounds using a receptor-ligand docking program, Sievgene [Y. Fukunishi, Y. Mikami, H. Nakamura, Similarities among receptor pockets and among compounds: analysis and application to in silico ligand screening, J. Mol. Graphics Modelling, 24 (2005) 34-45], and the results demonstrated that this method achieves a high hit ratio compared to uniform sampling. We prepared two new scores: the DeltaG score, designed to reproduce the protein-ligand binding free energy, and the hit-optimized score, designed to maximize the hit ratio of in silico screening. Using the Sievgene docking score, DeltaG score and hit-optimized score, the MTS method is more robust than the multiple active-site correction scoring method [G.P.A. Vigers, J.P. Rizzi, Multiple active site corrections for docking and virtual screening, J. Med. Chem., 47 (2004) 80-89].
Fukunishi
Yoshifumi
Y
Biological Information Research Center (BIRC), National Institute of Advanced Industrial Science and Technology (AIST), 2-41-6, Aomi, Tokyo 135-0064, Japan. y-fukunishi@jbirc.aist.go.jp
Mikami
Yoshiaki
Y
Kubota
Satoru
S
Nakamura
Haruki
H
D016208:Databases, Factual; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008024:Ligands; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D012107:Research Design
D008024:Ligands; D011506:Proteins