Computational Drug Discovery and Design

Benjamin P. Cossins, Alastair D. G. Lawson, Jiye Shi

Protein drug targets vary from highly structured to completely disordered; either way dynamics governs function. Hence, understanding the dynamical aspects of how protein targets function can enable improved interventions with drug molecules. Computational approaches offer highly detailed structural models of protein dynamics which are becoming more predictive as model quality and sampling power improve. However, the most advanced and popular models still have errors owing to imperfect parameter sets and often cannot access longer timescales of many crucial biological processes. Experimental approaches offer more certainty but can struggle to detect and measure lightly populated conformations of target proteins and subtle allostery. An emerging solution is to integrate available experimental data into advanced molecular simulations. In the future, molecular simulation in combination with experimental data may be able to offer detailed models of important drug targets such that improved functional mechanisms or selectivity can be accessed.