New Approaches to Virtual Screening
[caption id="attachment_39727" align="pull-left" width="320"] Figure 1: Schematic representation of virtual screening approaches within early-phase drug discovery.[/caption] Virtual screening (VS) aims to reduce the enormous virtual space of chemical compounds (a practical virtual library might comprise ~1015 molecules) to a more manageable number for further synthesis and screening against biological targets, which could lead to potential drug candidates. Although the origin of the computational methods goes back to the 1970s, the term “virtual screening” did not appear until 1997.1 Since then several successful case studies and approved drugs have demonstrated the relevance of computer-aided drug design (CADD). Additionally, the approach has proved useful in identifying relevant candidates for several drug repositioning applications.2 Despite recent developments, the potential of virtual screening in terms of helping medicinal chemists to develop new drugs in a time and cost-effective manner is still criticized by many.
There are two generally accepted approaches for virtual screening: ligand-based and structure-based (docking) methods. While ligand-based virtual screening (LBVS) uses 2D or 3D similarity searches between large compound databases and known actives, structure-based virtual screening (SBVS) applies different modeling techniques to mimic the binding interaction of a ligand to a biomolecular target. Hence, the biggest difference between LBVS and SBVS is that the latter requires structural information for the target, usually obtained from X-ray crystallography or nuclear magnetic resonance (NMR). If that information does not exist—which is often the case with membrane receptors such as GPCRs—one can also mimic this information with their homology models.3 Although a recent literature study has shown that docking is arguably the most widely used approach in early phase drug discovery, the same research also points out that LBVS methods in general yield a higher fraction of potent hits.4