Feb 2, 2016

Application of new informatics tools for identifying allosteric lead ligands of the c-Src kinase

BioRxiv : the Preprint Server for Biology
Lili X PengRuss B Altman


Recent molecular dynamics (MD) simulations of the catalytic domain of the c-Src kinase revealed intermediate conformations with a potentially druggable allosteric pocket adjacent to the C-helix, bound by 8-anilino-1-naphthalene sulfonate. Towards confirming the existence of this pocket, we have developed a novel lead enrichment protocol using new target and lead enrichment software to identify sixteen allosteric lead ligands of the c-Src kinase. First, Markov State Models analysis was used to identify the most statistically significant c-Src target conformations from all MD-simulated conformations. The most statistically relevant candidate MSM targets were then prioritized by assessing how well each reproduced binding poses of ligands specific to the ATP-competitive and allosteric pockets. The top-performing MSM targets, identified by receiver-operating curve analysis, were then used to screen the ZINC library of 13 million ″clean, drug-like ligands″, all of which prioritized based on their empirical scoring function, binding pose consistency across MSM targets, and strong hydrogen bonding and hydrophobic interactions with Src residues. The FragFEATURE knowledgebase of fragment-protein pocket interactions was then used to ident...Continue Reading

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Mentioned in this Paper

Computer Software
Molecular Dynamics
SRC gene
Molecular Helix
Men Who Have Sex With Men
Helix (Snails)
naphthalene-2-sulfonic acid
Hypersensitivity Reaction Mediated by Immune Complex
Src Homology Domains
Binding (Molecular Function)

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