Enhanced Virtual Screening by Combined Use of Two Docking Methods: Getting the Most on a Limited Budget

Abstract

Flexible ligand docking is a routine part of a modern structure-based lead discovery process. As of today, there are quite a number of commercial docking programs that can be used to screen large databases (hundreds of thousands to millions of compounds). However, limiting factors such as the number of commercial software licenses needed to perform docking simultaneously on multiple processors ("software cost") and the relatively long time required per molecule to get good results ("quality-to-speed") should be taken into account when planning a large docking run. How can we optimize the efficiency of selecting lead candidates by docking, in respect to the quality of the results, search speed, and software cost? We present a combination of two methods, our "fast-free-approximate" in-house docking program and the "slow-costly-accurate" ICM-Dock, as an example of one solution to the problem. Our proposed protocol is illustrated by a series of virtual screening experiments aimed at identifying active compounds in the MDL Drug Data Report database. In more than half of the 20 cases examined, at least several actives per protein target were identified in approximately 24 hours per target.