Abstract
The docking methods used in structure-based virtual database screening offer the ability to quickly and cheaply estimate the affinity and binding mode of a ligand for the protein receptor of interest, such as a drug target. These methods can be used to enrich a database of compounds, so that more compounds that are subsequently experimentally tested are found to be pharmaceutically interesting. In addition, like all virtual screening methods used for drug design, structure-based virtual screening can focus on curated libraries of synthesizable compounds, helping to reduce the expense of subsequent experimental verification. In this review, we introduce the protein-ligand docking methods used for structure-based drug design and other biological applications. We discuss the fundamental challenges facing these methods and some of the current methodological topics of interest. We also discuss the main approaches for applying protein-ligand docking methods. We end with a discussion of the challenging aspects of evaluating or benchmarking the accuracy of docking methods for their improvement, and discuss future directions.
Highlights
In the not-so-distant past, the effects of drugs on disease were known only by empirical observation.A century of subsequent research has revealed many intricacies in the working of cellular receptors and other drug targets, and likewise the methodology of finding small molecules that bind to specific targets has become increasingly complex
This development has been marked by the realization that the interacting surfaces of cellular receptors are chemically active and often flexible, and that these properties tend to be critical to the biological effects of the small molecules, or ligands, that bind to these receptors
It may be divided into two broad categories: de novo drug design, in which a novel compound is designed from scratch, and virtual database screening, in which computational methods are used to search through libraries of small molecules, in order to find those that are predicted to be the most likely to bind to a drug target of interest [1]
Summary
In the not-so-distant past, the effects of drugs on disease were known only by empirical observation. Rational drug design aims to use knowledge of the biological target of interest to optimize the process of finding new medications It may be divided into two broad categories: de novo drug design, in which a novel compound is designed from scratch, and virtual database screening, in which computational methods are used to search through libraries of small molecules, in order to find those that are predicted to be the most likely to bind to a drug target of interest [1]. Structure-based virtual screening typically employs docking software that is designed to explore the possible binding modes of a ligand within a binding site of interest and scoring functions that are used to estimate the affinity of the ligand for the binding site of interest [8,9,10,11] These sampling and scoring methods will be discussed in more detail . We end with some discussion and remarks about the future direction of the field
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