Virtual Screening and Its Integration with Modern Drug Design Technologies

Abstract

Drug discovery is a highly complex and costly process, which demands integrated efforts in several relevant aspects involving innovation, knowledge, information, technologies, expertise, R&D investments and management skills. The shift from traditional to genomics-and proteomics-based drug research has fundamentally transformed key R&D strategies in the pharmaceutical industry addressed to the design of new chemical entities as drug candidates against a variety of biological targets. Therefore, drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. The combination of available knowledge of several 3D protein structures with hundreds of thousands of small-molecules have attracted the attention of scientists from all over the world for the application of structure-and ligand-based drug design approaches. In this context, virtual screening technologies have largely enhanced the impact of computational methods applied to chemistry and biology and the goal of applying such methods is to reduce large compound databases and to select a limited number of promising candidates for drug design. This review provides a perspective of the utility of virtual screening in drug design and its integration with other important drug discovery technologies such as high-throughput screening (HTS) and QSAR, highlighting the present challenges, limitations, and future perspectives in medicinal chemistry.

Hit Identification and Optimization in Virtual Screening: Practical Recommendations Based on a Critical Literature Analysis

“…3, 4 Additionally, several recent studies have critically examined method design and application in virtual screening, presented practical recommendations and discussed shortcomings. 5–7 In this work, we instead focus on a critical analysis of the results of virtual screening, with particular attention given to identification of initial hits and hit optimization. Papers describing virtual screening results that were published from 2007 to 2011 were extracted from three databases, PubMed, Web of Science and Embase, using the MeSH terms and key word queries described in detail in the Supporting Information.…”

Footprinting of Inhibitor Interactions ofIn SilicoIdentified Inhibitors of Trypanothione Reductase ofLeishmaniaParasite

“…Structure-based virtual screening approach is primarily applied as a hit identification tool and also used in lead optimization; the aim is to reduce a large number of compounds to a smaller subset which can be biologically active against the target. The process of virtual screening to design inhibitors towards an enzyme involves modeling of the binding site of the inhibitor at the active site of the enzyme through docking procedures and scoring, ranking of those compounds to narrow down to a smaller subset which contains potential biologically active inhibitors [15, 16]. …”

Revealing protein networks and gene-drug connectivity in cancer from direct information

“…With more tumor tissues or cancer cell samples profiled, tissue specific analysis is feasible. We expect to combine this systems approach with a molecular approach to study protein interfaces in drug design 71, 72 in order to find possible compounds connected to target(s).…”