Reverse Screening Methods to Search for the Protein Targets of Chemopreventive Compounds

Abstract

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.

Keywords: drug design; methodology; online service; pharmacophore modeling; reverse docking; reverse screening; screening databases; shape similarity.

Figure 1

Compounds described in the manuscript.

Figure 2

The principle and workflow of shape screening, pharmacophore screening, and reverse docking.

Figure 3

Software and online services for shape screening, pharmacophore screening, and reverse docking.

Figure 4

The relationships among direct databases, indirect databases, and reference databases used in reverse screening.

Figure 5

The number and trend of applications using the three reverse screening methods and representative software since the year 2000.

Figure 6

Twenty-eight representative compounds obtained by the clustering of 57 bioactive compounds for target prediction by different reverse screening methods.