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

Abstract: 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 ap-plications of Virtual Screening (VS) within the context of SBDD and examine different procedures ranging from the ini-tial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of top-scoring hits. Recent improvements in structure-based virtual screening (SBVS) efficiency through ensemble docking, in-duced 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 en-able the discovery of new metabolic and signal transduction pathways and the design of inhibitors of multifunctional pro-teins 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 PI3K kinase. Second, we discuss a strategy for the identification of selective binders for the RXR nuclear receptor. In this protocol, a set of target structures is constructed for ensemble docking based on bindin