High-Throughput Docking Using Quantum Mechanical Scoring.

Today high-throughput docking is one of the most commonly used computational tools in drug lead discovery. While there has been an impressive methodological improvement in docking accuracy, docking scoring still remains an open challenge. Most docking programs are rooted in classical molecular mechanics. However, to better characterize protein-ligand interactions, the use of a more accurate quantum mechanical (QM) description would be necessary. In this work, we introduce a QM-based docking scoring function for high-throughput docking and evaluate it on 10 protein systems belonging to diverse protein families, and with different binding site characteristics. Outstanding results were obtained, with our QM scoring function displaying much higher enrichment (screening power) than a traditional docking method. It is acknowledged that developments in quantum mechanics theory, algorithms and computer hardware throughout the upcoming years will allow semi-empirical (or low-cost) quantum mechanical methods to slowly replace force-field calculations. It is thus urgently needed to develop and validate novel quantum mechanical-based scoring functions for high-throughput docking toward more accurate methods for the identification and optimization of modulators of pharmaceutically relevant targets.