Binding site characterization – similarity, promiscuity, and druggability

Abstract

Promiscuity as key to drug repurposing, off-target prediction, polypharmacology: What can be learned based on the comparison of binding sites and the description of their properties? Herein, we discuss binding site similarities with a special focus on medicinal chemistry.

Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site

“…The fundamental principle of drug discovery is that biologically active ligands are complimentary in molecular features and shape to the receptor. These can include physiochemical properties such as hydrophobicity, size, as well as the enclosure of the binding pocket and its promiscuity 33,34 . A strictly predominantly hydrophobic pocket might indicate a promiscuous binding site that may accommodate a wide-varying of ligands in different modes, some hydrophobic patches are still nevertheless ideal for ligand design.…”

Unlocking COVID therapeutic targets: A structure-based rationale against SARS-CoV-2, SARS-CoV and MERS-CoV Spike

“…Pockets with a DGSS druggability score ≥ 0.4 were considered druggable [96] . The druggability threshold was previously defined by Volkamer and the methodology was applied with success by other authors [90] , [96] , [98] , [99] , [100] .…”

Compounds With Multitarget Activity: Structure-Based Analysis and Machine Learning

“…At the structural level, promiscuity can be viewed from a ligand [17,18] or target perspective [17,20], which is not mutually exclusive. Several studies have revealed that promiscuous ligands often bind to similar binding sites in proteins [17,21,22]. If proteins belong to the same family they typically have similar binding sites (and functions), which favor compound binding to related targets.…”