The previously developed Scorpion approach1, which predicts ligand affinity based on the quantitative analysis of molecular interaction networks in a protein-ligand binding site, has been extended to help target binding hot-spots and rank hits from ligand design experiments that use fragment scanning.  We further fine-tune our experiments with a better understanding of binding site flexibility, obtained from the analyses of experimental structures using high-quality overlays and measuring deviations in atomic coordinates about average structures.   Additionally, we aim to accurately predict flexibility, also using network-based descriptors.  Our goal is to be able to routinely use our models of network cooperativity and flexibility to discover new chemical entities that otherwise would not be found using simple, additive structure-activity relationships and a more rigid model of a binding site. 1. http://dx.doi.org/10.1021/ci200319e

Ligand design incorporating network concepts and binding site flexibility

247th National Meeting (2014)

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