Biasing conformational ensembles towards bioactive-like conformers for ligand-based drug design

In silico or virtual screening has become a common practice in contemporary computer-aided drug discovery efforts and currently constitutes a reasonably mature paradigm. Application of ligand-based approaches to virtual screening requires the ability to identify the bioactive conformers of drug-like compounds as these conformers are expected to elicit the biological activity. However, given the complexity of the energy potential surfaces of such ligands and in particular those exhibiting some degree of flexibility and the limitation of contemporary energy functions, this is not an easy task.

The current contribution provides an in-depth review of recent developments in the field of generating conformational ensembles of drug-like compounds with a particular emphasis of focusing such ensembles on bioactive conformers using both energy and structural criteria. The literature reviewed in this manuscript roughly covers the last decade.

Readers of this review will gain an appreciation for the complexity of identifying bioactive conformers of drug-like compounds and an exposure to the different computational methods which were developed in order to tackle this problem as well as to the remaining challenges in this field.

The identification of ensembles of bioactive conformers of drug-like compounds is far from being a solved problem. Recent research has advanced the field to the point where bioactive conformers could be readily identified from within conformational ensembles generated by contemporary computational tools. However, as such conformers are inevitably accompanied by many other non-relevant conformations, a focusing mechanism is required. New methods in this field are showing promise but more work is clearly needed. New research lines are proposed which are believed to enhance the performances and with it the usefulness of 3D ligand-based methods in drug discovery and development.