Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C
| العنوان: | Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C |
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| المؤلفون: | J. Schroeder, Stefan Gradl, Volker Badock, Knut Eis, Benjamin Bader, Hans Briem, Clara D. Christ, Patrick Steigemann, Roman C. Hillig, Duy Nguyen, Jérémie Mortier, Marcus Bauser, Anders Friberg, Dieter Moosmayer, Franziska Siegel |
| المصدر: | ChemMedChem. 15:827-832 |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Pharmacology, 010405 organic chemistry, Chemistry, Organic Chemistry, Allosteric regulation, Naphthyridinone, Druggability, Computational biology, 01 natural sciences, Biochemistry, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Workflow, Covalent bond, Docking (molecular), Drug Discovery, Molecular Medicine, General Pharmacology, Toxicology and Pharmaceutics, Pharmacophore |
| الوصف: | Due to its frequent mutations in multiple lethal cancers, KRAS is one of the most-studied anticancer targets nowadays. Since the discovery of the druggable allosteric binding site containing a G12C mutation, KRASG12C has been the focus of attention in oncology research. We report here a computationally driven approach aimed at identifying novel and selective KRASG12C covalent inhibitors. The workflow involved initial enumeration of virtual molecules tailored for the KRAS allosteric binding site. Tools such as pharmacophore modeling, docking, and free-energy perturbations were deployed to prioritize the compounds with the best profiles. The synthesized naphthyridinone scaffold showed the ability to react with G12C and inhibit KRASG12C . Analogues were prepared to establish structure-activity relationships, while molecular dynamics simulations and crystallization of the inhibitor-KRASG12C complex highlighted an unprecedented binding mode. |
| تدمد: | 1860-7187 1860-7179 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::cd3a78dae00c2acf021360ef88b2d38f https://doi.org/10.1002/cmdc.201900727 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........cd3a78dae00c2acf021360ef88b2d38f |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 18607187 18607179 |
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