Challenges, Applications, and Recent Advances of Protein-Ligand Docking in Structure-Based Drug Design

Abstract

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.

Understanding the challenges of protein flexibility in drug design

“…Since the docking procedure is repeated multiple times when screening a large library of ligands, VS imposes a trade-off between the speed of the docking method and its accuracy [6]. Consequently, exploring large-scale structural changes and folding events during conformational sampling can represent a detrimental computational burden.…”

“…Sampling and scoring engender different challenges, but have a combined influence on docking accuracy and performance [7], [8]. Issues related to scoring have been examined in numerous reviews [4]- [6], [9], [10], and will not be discussed here. Instead, the present paper focuses on sampling methods.…”

“…Sampling consists of exploring (some of) the structural degrees of freedom (DoFs) of a protein-ligand complex and predicting its binding mode [5]. Scoring consists of estimating the strength of the binding interaction (binding energy) for a given binding mode [6]. Sampling and scoring engender different challenges, but have a combined influence on docking accuracy and performance [7], [8].…”

Computational allosteric ligand binding site identification on Ras proteins

“…Structure-based computer-aided drug design (CADD) approaches can expedite the process and reduce cost [61]. As a result, high-throughput virtual screening (HTVS) of ligand libraries has become an integral part of drug design programs in both industry and academic laboratories [62,63].…”

Molecular Docking Studies of Selected Medicinal Drugs as Dengue Virus-2 Protease Inhibitors

“…In silico molecular docking is a good tool to predict and match the desired binding site, understanding possible conformation of the compounds and further clarifies the binding interactions in the binding pocket (Grinter & Zou 2014). Structural homology model built by Heh et al (2013), namely DH-1, was utilized instead of its crystal structure, due to the missing loop between Ile76 and Ser85 of the NS2B region (Erbel et al 2006).…”