Structure-based lead optimization virtual screening

Hot Spot Analysis of Protein-binding Sites as a Prerequisite for Structure-based Virtual Screening and Lead Optimization... 

Drug design, based on crystal structures of target incorporated with substrate or inhibitor (primarily for enzymes). More useful for lead optimization than for primary discovery. Can be configured to serve as electronic ( virtual ) random screen. 1980s-present. 

The conceptual basis for similarity analysis is provided by the similarity-property principle that states that similar molecules have similar biological activity.This rather intuitive principle has been widely accepted and substantiated by a wealth of observations. The success of many similarity-based virtual screening calculations can only be rationalized on the basis of this principle. However, minor modifications in molecular structure can dramatically alter the biological activity of a small molecule. This situation is exploited in lead optimization elforts, but limits the potential of similarity methods. These considerations also suggest that there must be fundamental dilferences between the structure-activity relationships (SARs). Thus, difierent types of SARs are expected to critically determine the success of similarity methods and systematic SAR analysis helps to better understand on a case-by-case basis why similarity methods might succeed or fail. 

Besides virtual screening of ligand libraries, docking is extremely useful for lead optimization. Successful docking can elucidate the important interactions between lead molecules and the target, explain important features of the structure activity relationships (SAR), and consequently help to design new molecules. Other than docking, useful receptor based VLS tools include MD simulation, MC simulation, and QM/MM calculation. 

Brenk, R., Klebe, G. Hot spot analysis of protein-binding sites as a prerequisite for structure-based virtual screening and lead optimization. Meth. Prin. Med. Chem. 2006, 32, 171—192. 

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