High-Performance Drug Discovery: Computational Screening by Combining Docking and Molecular Dynamics Simulations

Abstract

Lead discovery is one of the most important processes in rational drug design. To improve the rate of the detection of lead compounds, various technologies such as high-throughput screening and combinatorial chemistry have been introduced into the pharmaceutical industry. However, since these technologies alone may not improve lead productivity, computational screening has become important. A central method for computational screening is molecular docking. This method generally docks many flexible ligands to a rigid protein and predicts the binding affinity for each ligand in a practical time. However, its ability to detect lead compounds is less reliable. In contrast, molecular dynamics simulations can treat both proteins and ligands in a flexible manner, directly estimate the effect of explicit water molecules, and provide more accurate binding affinity, although their computational cost and time are significantly greater than those of molecular docking. Therefore, we developed a special purpose computer MDGRAPE-3 for molecular dynamics simulations and applied it to computational screening. In this paper, we report an effective method for computational screening; this method is a combination of molecular docking and massive-scale molecular dynamics simulations. The proposed method showed a higher and more stable enrichment performance than the molecular docking method used alone.