Improving small molecule virtual screening strategies for the next generation of therapeutics

The new generation of post-genomic targets, such as protein-protein interactions (PPIs), often require new chemotypes not well represented in current compound libraries. This is one reason for why traditional high throughput screening (HTS) approaches are not more successful in delivering medicinal chemistry starting points for PPIs. In silico screening methods of an expanded chemical space are then potential alternatives for developing novel chemical probes to modulate PPIs. In this review, we report on the state-of-the-art pipelines for virtual screening, emphasizing prospectively validated methods capable of addressing the challenge of drugging difficult targets in the human interactome. Collectively, we show that optimal strategies for structure based virtual screening vary depending on receptor structure and degree of flexibility.