Structure-Based Virtual Screening for Drug Discovery: Principles, Applications and Recent Advances

By Evanthia Lionta, George M. Spyrou, D. Vassilatis, Zoe Cournia. 2014

968 citations recorded by the source corpus.

Structure-based drug discovery (SBDD) is becoming an essential tool in assisting fast and cost-efficient lead discovery and optimization. The application of rational, structure-based drug design is proven to be more efficient than the traditional way of drug discovery since it aims to understand the molecular basis of a disease and utilizes the knowledge of the three-dimensional structure of the biological target in the process. In this review, we focus on the principles and applications of Virtual Screening (VS) within the context of SBDD and examine different procedures ranging from the initial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of topscoring hits. Recent improvements in structure-based virtual screening (SBVS) efficiency through ensemble docking, induced fit and consensus docking are also discussed. The review highlights advances in the field within the framework of several success studies that have led to nM inhibition directly from VS and provides recent trends in library design as well as discusses limitations of the method. Applications of SBVS in the design of substrates for engineered proteins that enable the discovery of new metabolic and signal transduction pathways and the design of inhibitors of multifunctional proteins are also reviewed. Finally, we contribute two promising VS protocols recently developed by us that aim to increase inhibitor selectivity. In the first protocol, we describe the discovery of micromolar inhibitors through SBVS designed to inhibit the mutant H1047R PI3Kα kinase. Second, we discuss a strategy for the identification of selective binders for the RXRα nuclear receptor. In this protocol, a set of target structures is constructed for ensemble docking based on binding site shape characterization and clustering, aiming to enhance the hit rate of selective inhibitors for the desired protein target through the SBVS process.

Subfields: Computational Theory and Mathematics, Computer Vision and Pattern Recognition, Organic Chemistry, Pharmacology

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Citations in the corpus

Molecular Docking and Structure-Based Drug Design Strategies (2015, methodology): “In SBVS, the compound database is docked into a previously selected target binding site [167].”
Ligand biological activity predicted by cleaning positive and negative chemical correlations (2019, background): “Structure-based approaches require knowledge of the receptor structure and the binding site, and they predict the binding free energy by modeling protein–ligand interactions (6–8).”
Role of computer-aided drug design in modern drug discovery (2015, background): “…to be a big part of the drug discovery process in the pharmaceutical industry due to its high success rate, lack of primary understanding of the molecular mechanism behind the activity of the identiﬁed hits can hamper the search of promising candidates (Macarron et al. 2011; Lionta et al. 2014).”
A Structure-Based Drug Discovery Paradigm (2019, background): “SBDD is a more specific, efficient, and rapid process for lead discovery and optimization (Figure 1) because it deals with the 3D structure of a target protein and knowledge about the disease at the molecular level [9].”
Recent applications of deep learning and machine intelligence on in silico drug discovery: methods, tools and databases (2018, background): “pounds to model the interactions [31, 32], Figure 2.”
Structure-Based Virtual Screening: From Classical to Artificial Intelligence (2020, methodology): “The disadvantages can be highlighted as the following: I Some tools work best in speciﬁc cases, but not in more general cases (Lionta et al., 2014).”