Using reverse docking for target identification and its applications for drug discovery

ABSTRACT

Introduction: In contrast to traditional molecular docking, inverse or reverse docking is used for identifying receptors for a given ligand among a large number of receptors. Reverse docking can be used to discover new targets for existing drugs and natural compounds, explain polypharmacology and the molecular mechanism of a substance, find alternative indications of drugs through drug repositioning, and detecting adverse drug reactions and drug toxicity.

Areas covered: In this review, the authors examine how reverse docking methods have evolved over the past fifteen years and how they have been used for target identification and related applications for drug discovery. They discuss various aspects of target databases, reverse docking tools and servers.

Expert opinion: There are several issues related to reverse docking methods such as target structure dataset construction, computational efficiency, how to include receptor flexibility, and most importantly, how to properly normalize the docking scores. In order for reverse docking to become a truly useful tool for the drug discovery, these issues need to be adequately resolved.

KEYWORDS:

• Reverse docking
• target identification
• drug discovery
• binding pocket
• target database

Article highlights

• Reverse docking approach is a computational target identification method useful for adverse side effect prediction, drug repositioning, and lead optimization.

• Defining a proper set of target structures and their binding pockets is essential not only for the efficiency but for the accuracy of reverse docking.

• Various reverse docking tools and servers are available with various target databases, binding site definitions, and scoring schemes.

• Reverse docking is utilized in multiple research areas for identifying novel targets, explaining off-target effects of drugs, mechanisms of drug actions and drug toxicity.

• Reverse docking method is able to predict the binding site and pose of a ligand to the receptor which are useful sources for lead optimization.

• Problematic aspects of reverse docking include high computational time, inter-protein noises of docking scores, and deficiency of available target structures.

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Declaration of interest

This work was supported by the Bio-Synergy Research Project (2012M3A9C4048758) of the Ministry of Science, ICT and Future Planning through the National Research Foundation in Republic of Korea. The authors have no other 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 apart from those disclosed.