Emerging methods for ensemble-based virtual screening

Abstract

Ensemble based virtual screening refers to the use of conformational ensembles from crystal structures, NMR studies or molecular dynamics simulations. It has gained greater acceptance as advances in the theoretical framework, computational algorithms, and software packages enable simulations at longer time scales. Here we focus on the use of computationally generated conformational ensembles and emerging methods that use these ensembles for discovery, such as the Relaxed Complex Scheme or Dynamic Pharmacophore Model. We also discuss the more rigorous physics-based computational techniques such as accelerated molecular dynamics and thermodynamic integration and their applications in improving conformational sampling or the ranking of virtual screening hits. Finally, technological advances that will help make virtual screening tools more accessible to a wider audience in computer aided drug design are discussed.

Fig. 1

General workflow for ensemble-based virtual screen experiment. Blue arrows indicate size of data sets (i.e. increasing or decreasing) at each step; * denotes emerging methods that have not yet been tested. (AMD: accelerated molecular dynamics, GB MD: generalized Born molecular dynamics, RMSD: root-mean-square-deviation, ZINC – ZINC Is Not Commerical, ACD: Available Chemical Database, NCI: National Cancer Institute, MM-PB(GB)SA: Molecular Mechanics – Poisson-Boltzmann (Generalized Born) Surface Area).

Fig. 2

MD generated conformational ensemble used for virtual screening of the flexible avian influenza neuraminidase receptor (PDB 2HU4). Closed binding pocket (orange, left panel) from crystal structures; wide open 150- and 430-loop areas (grey, right panel) from MD simulations [69]. Select compounds from the virtual screen are shown docked to these areas; oseltamivir shown in dark gray (open pocket highlighted in red circle).

Fig. 3

Evolution of publicly available compute power since 1993. Hardware advances (machine name, number of processors) are shown in grey, whereas system advances (example system, number of atoms, and average timescale for simulations) are shown in white.