Novel Allosteric Sites on Ras for Lead Generation
Barry J. Grant,Suryani Lukman,Suryani Lukman,Harrison J. Hocker,Jaqueline Sayyah,Joan Heller Brown,J. Andrew McCammon,Alemayehu A. Gorfe +7 more
TLDR
The hypothesis that the chosen binders can inhibit the downstream signaling activity of Ras is confirmed and it is proposed that the predicted allosteric sites are viable targets for the development and optimization of new drugs.Abstract:
Aberrant Ras activity is a hallmark of diverse cancers and developmental diseases. Unfortunately, conventional efforts to develop effective small molecule Ras inhibitors have met with limited success. We have developed a novel multi-level computational approach to discover potential inhibitors of previously uncharacterized allosteric sites. Our approach couples bioinformatics analysis, advanced molecular simulations, ensemble docking and initial experimental testing of potential inhibitors. Molecular dynamics simulation highlighted conserved allosteric coupling of the nucleotide-binding switch region with distal regions, including loop 7 and helix 5. Bioinformatics methods identified novel transient small molecule binding pockets close to these regions and in the vicinity of the conformationally responsive switch region. Candidate binders for these pockets were selected through ensemble docking of ZINC and NCI compound libraries. Finally, cell-based assays confirmed our hypothesis that the chosen binders can inhibit the downstream signaling activity of Ras. We thus propose that the predicted allosteric sites are viable targets for the development and optimization of new drugs.read more
Citations
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Drugging the undruggable Ras: mission possible?
TL;DR: This Review summarizes the progress and the promise of five key approaches for the development of RAS-inhibitory molecules and addresses the issue of whether blocking RAS membrane association is a viable approach.
Journal ArticleDOI
Molecular dynamics simulations and drug discovery
TL;DR: This review discusses the many roles atomistic computer simulations of macromolecular receptors and their associated small-molecule ligands can play in drug discovery, including the identification of cryptic or allosteric binding sites, the enhancement of traditional virtual-screening methodologies, and the direct prediction of small-Molecule binding energies.
Journal ArticleDOI
Ras Conformational Ensembles, Allostery, and Signaling.
Shaoyong Lu,Shaoyong Lu,Hyunbum Jang,Serena Muratcioglu,Attila Gursoy,Ozlem Keskin,Ruth Nussinov,Ruth Nussinov,Jian Zhang +8 more
TL;DR: This review focuses on data that have accumulated over the past few years pertaining to the conformational ensembles and the allosteric regulation of Ras proteins and their interpretation from a conformational landscape standpoint.
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Equilibrium fluctuations of a single folded protein reveal a multitude of potential cryptic allosteric sites
TL;DR: It is demonstrated that Markov state models built from extensive computer simulations can identify prospective cryptic sites from the equilibrium fluctuations of three medically relevant proteins—β-lactamase, interleukin-2, and RNase H—even in the absence of any ligand.
Journal ArticleDOI
Small-molecule modulation of Ras signaling
TL;DR: Recently, new cavities on Ras for small-molecule ligands were identified, and selective direct targeting of mutated K-Ras(G12C) has become possible for the first time, and impairment of Ras spatial organization via targeting the prenyl-binding Ras chaperone PDEδ has opened a fresh perspective in anticancer research.
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