Virtual screening (VS) is becoming an increasingly important approach for identifying and selecting biologically active molecules against specific pharmaceutically relevant targets. Compared to conventional high throughput screening techniques, in silico screening is fast and inexpensive, and is increasing in popularity in early-stage drug discovery endeavours. This paper reviews and discusses recent trends and developments in three-dimensional (3D) receptor-based and ligand-based VS methodologies. First, we describe the concept of accessible chemical space and its exploration. We then describe 3D structural ligand-based VS techniques, hybrid approaches, and new approaches to exploit additional knowledge that can now be found in large chemogenomic databases. We also briefly discuss some potential issues relating to pharmacokinetics, toxicity profiling, target identification and validation, inverse docking, scaffold-hopping and drug re-purposing. We propose that the best way to advance the state of the art in 3D VS is to integrate complementary strategies in a single drug discovery pipeline, rather than to focus only on theoretical or computational improvements of individual techniques. Two recent 3D VS case studies concerning the LXR-β receptor and the CCR5/CXCR4 HIV co-receptors are presented as examples which implement some of the complementary methods and strategies that are reviewed here.
Keywords: 3D-QSAR, 3D shape matching, chemical libraries, chemical spaces, computer-aided drug design, conformational flexibility, docking, knowledge-based drug design, ligand-based drug design, molecular dynamics, pharmacophores, structurebased drug design, virtual screening