Virtual Screening

Virtual screening (VS) is a computational technique used in drug discovery research. By using computers, it deals with the quick search of large libraries of chemical structures in order to identify those structures which are most likely to bind to a drug target, typically a protein receptor or enzyme.

Virtual screening has become an integral part of the drug discovery process. Related to the more general and long pursued concept of database searching, the term "virtual screening" is relatively new. Walters, et al. define virtual screening as "automatically evaluating very large libraries of compounds" using computer programs. As this definition suggests, VS has largely been a numbers game focusing on questions like how can we filter down the enormous chemical space of over 1060 conceivable compounds to a manageable number that can be synthesized, purchased, and tested. Although filtering the entire chemical universe might be a fascinating question, more practical VS scenarios focus on designing and optimizing targeted combinatorial libraries and enriching libraries of available compounds from in-house compound repositories or vendor offerings.

The aim of virtual screening is to identify molecules of novel chemical structure that bind to the macromolecular target of interest. Thus, success of a virtual screen is defined in terms of finding interesting new scaffolds rather than many of these hits. Interpretations of virtual screening accuracy should therefore be considered with caution. Low hit rates of interesting scaffolds are clearly preferable over high hit rates of already known scaffolds.

Most virtual screening studies in the literature are retrospective. In these studies, the performance of a VS technique is measured by its ability to retrieve a small set of previously known molecules with affinity to the target of interest (active molecules or just actives) from a library containing a much higher proportion of assumed inactives or decoys. By contrast, in prospective applications of virtual screening, the resulting hits are subjected to experimental confirmation (e.g., IC₅₀ measurements). There is consensus that retrospective benchmarks are not good predictors of prospective performance and consequently only prospective studies constitute conclusive proof of the suitability of a technique for a particular target.