Flexible receptor docking for drug discovery

Molecular docking has become a popular method for virtual screening. Docking small molecules to a rigid biological receptor is fast but could produce many false negatives and identify less diverse compounds. Flexible receptor docking has alleviated this problem.

This article focuses on reviewing ensemble docking as an approximate but inexpensive method to incorporate receptor flexibility in molecular docking. It outlines key features and recent advances of this method and points out problem areas that need to be addressed to make it even more useful in drug discovery.

Among the different methods introduced for flexible receptor docking, ensemble docking represents one of the most popular approaches, especially for high-throughput virtual screening. One can generate structural ensembles by using experimental structures, by structural modeling and by various types of molecular simulations. In building a structural ensemble, a judicious choice of the structures to be included can improve performance. Furthermore, reducing the size of the structural ensemble can cut computational costs, and removing the structures that can bind few ligands well could enrich the number of true actives identified by ensemble docking. The ability of ensemble docking to identify more true positives at the top of a rank-ordered list also depends on the choice of the methods to score and rank compounds, an area that needs further research.