The compromise of virtual screening and its impact on drug discovery

ABSTRACT

Introduction: Docking and structure-based virtual screening (VS) have been standard approaches in structure-based design for over two decades. However, our understanding of the limitations, potential, and strength of these techniques has enhanced, raising expectations.

Areas covered: Based on a survey of reports in the past five years, we assess whether VS: (1) predicts binding poses in agreement with crystallographic data (when available); (2) is a superior screening tool, as often claimed; (3) is successful in identifying chemical scaffolds that can be starting points for subsequent lead optimization cycles. Data shows that knowledge of the target and its chemotypes in postprocessing lead to viable hits in early drug discovery endeavors.

Expert opinion: VS is capable of accurate placements in the pocket for the most part, but does not consistently score screening collections accurately. What matters is capitalization on available resources to get closer to a viable lead or optimizable series. Integration of approaches, subjective hit selection guided by knowledge of the receptor or endogenous ligand, libraries driven by experimental guides, validation studies to identify the best docking/scoring that reproduces experimental findings, constraints regarding receptor–ligand interactions, thoroughly designed methodologies, and predefined cutoff scoring criteria strengthen VS’s position in pharmaceutical research.

KEYWORDS:

• Structure-based virtual screening
• hit identification
• lead optimization
• screening libraries
• preprocessing
• postprocessing
• prospective virtual screening
• drug discovery

Article Highlights

• The known pitfalls of virtual screening are, in practice, circumvented by the coupling of chemical intuition, upfront knowledge of the target system, interrogation of similar chemical space, and fast computing, based on analyses of literature from 2014 to 2018.

• The very few studies where the predicted binding modes were experimentally confirmed are inconclusive. The poses are accurate at times, and other times not enough information is provided, and/or the investigators make inferences from homologous ligand-target complexes. Given that the top-ranked pose or very few per compound are reported per screen, this suggests that virtual screening results have the potential to lead down a suboptimal path in lead optimization, if other methods do not complement it.

• The claim that high-throughput screening is inferior to virtual screening towards hit identification should be considered with caution. We were unable to find studies where head-to-head comparative data were presented with the same library and without any prefiltering done on the virtual libraries.

• Several successful studies highlight the importance of integrating information stemming from homologous targets, previously evaluated chemical chemotypes for the target under investigation, processed virtual libraries, and careful postprocessing.

• Hits identified through virtual screening experiments have undergone several rounds of optimization resulting in leads with the potential for further optimization.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.