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

Abstract

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

  • References
  • Citations

References

  • We're still populating references for this paper, please check back later.
  • References
  • Citations

Citations

  • This paper may not have been cited yet.

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)

About this Paper

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.

BioHub - Researcher Network

The Chan-Zuckerberg Biohub aims to support the fundamental research and develop the technologies that will enable physicians to cure, prevent, or manage all diseases in our childrens' lifetimes. The CZ Biohub brings together researchers from UC Berkeley, Stanford, and UCSF. Find the latest research from the CZ Biohub researcher network here.