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Computationally Empowered Workflow Identifies Novel Covalent Allosteric Binders for KRASG12C.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-04-01 , DOI: 10.1002/cmdc.201900727 Jérémie Mortier 1 , Anders Friberg 1 , Volker Badock 1 , Dieter Moosmayer 1 , Jens Schroeder 1 , Patrick Steigemann 1 , Franziska Siegel 1 , Stefan Gradl 1 , Marcus Bauser 1 , Roman C Hillig 1 , Hans Briem 1 , Knut Eis 1 , Benjamin Bader 1 , Duy Nguyen 1 , Clara D Christ 1
ChemMedChem ( IF 3.6 ) Pub Date : 2020-04-01 , DOI: 10.1002/cmdc.201900727 Jérémie Mortier 1 , Anders Friberg 1 , Volker Badock 1 , Dieter Moosmayer 1 , Jens Schroeder 1 , Patrick Steigemann 1 , Franziska Siegel 1 , Stefan Gradl 1 , Marcus Bauser 1 , Roman C Hillig 1 , Hans Briem 1 , Knut Eis 1 , Benjamin Bader 1 , Duy Nguyen 1 , Clara D Christ 1
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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.
中文翻译：
计算授权的工作流程确定了 KRASG12C 的新型共价变构结合剂。
由于 KRAS 在多种致命癌症中频繁发生突变，因此成为当今研究最多的抗癌靶点之一。自从发现含有 G12C 突变的可药物变构结合位点以来，KRASG12C 一直是肿瘤学研究关注的焦点。我们在这里报告了一种计算驱动的方法，旨在识别新型和选择性的 KRASG12C 共价抑制剂。该工作流程涉及针对 KRAS 变构结合位点定制的虚拟分子的初始计数。使用药效团建模、对接和自由能扰动等工具来优先考虑具有最佳特征的化合物。合成的萘啶酮支架表现出与G12C反应并抑制KRASG12C的能力。制备类似物以建立结构-活性关系，而抑制剂-KRASG12C 复合物的分子动力学模拟和结晶突出了前所未有的结合模式。
更新日期：2020-04-01
中文翻译：
计算授权的工作流程确定了 KRASG12C 的新型共价变构结合剂。
由于 KRAS 在多种致命癌症中频繁发生突变，因此成为当今研究最多的抗癌靶点之一。自从发现含有 G12C 突变的可药物变构结合位点以来，KRASG12C 一直是肿瘤学研究关注的焦点。我们在这里报告了一种计算驱动的方法，旨在识别新型和选择性的 KRASG12C 共价抑制剂。该工作流程涉及针对 KRAS 变构结合位点定制的虚拟分子的初始计数。使用药效团建模、对接和自由能扰动等工具来优先考虑具有最佳特征的化合物。合成的萘啶酮支架表现出与G12C反应并抑制KRASG12C的能力。制备类似物以建立结构-活性关系，而抑制剂-KRASG12C 复合物的分子动力学模拟和结晶突出了前所未有的结合模式。
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