Accurate Scoring in Seconds with the Fragment Molecular Orbital and Density-Functional Tight-Binding Methods.

The accurate evaluation of receptor-ligand interactions is an essential part of rational drug design. While quantum mechanical (QM) methods have been a promising means by which to achieve this, traditional QM is not applicable for large biological systems due to its high computational cost. Here, the fragment molecular orbital (FMO) method has been combined with the density-functional tight-binding (DFTB) method to compute energy calculations of biological systems in seconds. FMO-DFTB outperformed GBVI/WSA in identifying a set of 10 binders versus a background of 500 decoys applied to human k-opioid receptor. The significant increase in the speed and the high accuracy achieved with FMO-DFTB calculations allows FMO to be applied in areas of drug discovery that were not previously accessible to traditional QM methodologies. For the first time, it is now possible to perform FMO calculations in a high-throughput manner.