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This article is a systematic review of reverse screening methods used to search for the protein targets of chemopreventive compounds or drugs. Typical chemopreventive compounds include components of traditional Chinese medicine, natural compounds and Food and Drug Administration (FDA)-approved drugs. Such compounds are somewhat selective but are predisposed to bind multiple protein targets distributed throughout diverse signaling pathways in human cells. In contrast to conventional virtual screening, which identifies the ligands of a targeted protein from a compound database, reverse screening is used to identify the potential targets or unintended targets of a given compound from a large number of receptors by examining their known ligands or crystal structures. This method, also known as in silico or computational target fishing, is highly valuable for discovering the target receptors of query molecules from terrestrial or marine natural products, exploring the molecular mechanisms of chemopreventive compounds, finding alternative indications of existing drugs by drug repositioning, and detecting adverse drug reactions and drug toxicity. Reverse screening can be divided into three major groups: shape screening, pharmacophore screening and reverse docking. Several large software packages, such as Schrödinger and Discovery Studio; typical software/network services such as ChemMapper, PharmMapper, idTarget, and INVDOCK; and practical databases of known target ligands and receptor crystal structures, such as ChEMBL, BindingDB, and the Protein Data Bank (PDB), are available for use in these computational methods. Different programs, online services and databases have different applications and constraints. Here, we conducted a systematic analysis and multilevel classification of the computational programs, online services and compound libraries available for shape screening, pharmacophore screening and reverse docking to enable non-specialist users to quickly learn and grasp the types of calculations used in protein target fishing. In addition, we review the main features of these methods, programs and databases and provide a variety of examples illustrating the application of one or a combination of reverse screening methods for accurate target prediction.

Molecular docking is an established in silico structure-based method widely used in drug discovery. Docking enables the identification of novel compounds of therapeutic interest, predicting ligand-target interactions at a molecular level, or delineating structure-activity relationships (SAR), without knowing a priori the chemical structure of other target modulators. Although it was originally developed to help understanding the mechanisms of molecular recognition between small and large molecules, uses and applications of docking in drug discovery have heavily changed over the last years. In this review, we describe how molecular docking was firstly applied to assist in drug discovery tasks. Then, we illustrate newer and emergent uses and applications of docking, including prediction of adverse effects, polypharmacology, drug repurposing, and target fishing and profiling, discussing also future applications and further potential of this technique when combined with emergent techniques, such as artificial intelligence.

The development of target-fishing approaches, aimed at identifying the possible protein targets of a small molecule, represents a hot topic in medicinal chemistry. A successful target-fishing approach would allow for the elucidation of the mechanism of action of all therapeutically interesting compounds for which the actual target is still unknown. Moreover, target-fishing would be essential for preventing adverse effects of drug candidates, by predicting their potential off-targets, and it would speed up drug repurposing campaigns. However, due to the huge number of possible protein targets that a small-molecule might interact with, experimental target-fishing approaches are out of reach. In silico target-fishing represents a valuable alternative, and examples of receptor-based approaches, exploiting the large number of crystallographic protein structures determined to date, have been reported in the literature. To the best of our knowledge, no proper evaluation of such approaches is, however, reported yet. In the present work, we extensively assessed the reliability of docking-based target-fishing strategies. For this purpose, a set of X-ray structures belonging to different targets was selected, and a dataset of compounds, including 10 experimentally active ligands for each target, was created. A target-fishing benchmark database was then obtained, and used to assess the performance of 13 different docking procedures, in identifying the correct target of the dataset ligands. Moreover, a consensus docking-based target-fishing strategy was developed and evaluated. The analysis highlighted that specific features of the target proteins could affect the reliability of the protocol, which however, proved to represent a valuable tool in the proper applicability domain. Our study represents the first extensive performance assessment of docking-based target-fishing approaches, paving the way for the development of novel efficient receptor-based target fishing strategies.