The focal adhesion kinase-growth factor receptor 2 (FAK-Grb2) protein-protein interaction is implicated in pathogenesis of stress-induced cardiac hypertrophy. The focal adhesion targeting (FAT) domain of FAK unfolds to form a structural intermediate that interacts with a multibinding hot spot in the SH2 domain of Grb2. Disruption of the Grb2-FAT interaction is a therapeutic strategy for prevention of pathological cardiac hypertrophy. A pharmacophore was generated on the basis of structural and electrostatic properties of FAT bound to FAK using the Forge tool (Cresset). This pharmacophore was used as a query for Blaze server (Cresset) to screen a selectively enriched chemical library of 4,32,508 small molecules. The compounds selected were further filtered by hierarchical flexible docking approach using AutoDock v4. From the favorably docked compounds, five were selected on the basis of good adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties using SwissADME, MedChem Designer v.3, and MOLINSPIRATION. Stability of the binding mode of the inhibitors was further confirmed by molecular dynamic simulation study with AMBER v15 for a simulation time of 50 ns in aqueous environment. PM2307 was identified as the best inhibitor in terms of pharmacophoric features, dock score, and in silico ADMET analysis. The calculated binding affinity of PM2307 was better than that of the FAT-Grb2 complex as well as a previously reported small molecule inhibitor. PM2307 is also a quinolyl derivative sharing a similar scaffold with ofloxacin drugs, asserting its drug-like properties. Thus, it was proposed as a lead compound for development of drugs for pathological cardiac hypertrophy.

中文翻译：

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在计算机筛查中确定生长因子受体2-局部黏着激酶相互作用的抑制剂，用于病理性心肌肥大的治疗。

粘着斑激酶-生长因子受体2（FAK-Grb2）蛋白质-蛋白质相互作用与应激诱导的心脏肥大的发病机理有关。FAK的粘着靶向（FAT）域展开以形成结构中间体，该中间体与Grb2的SH2域中的多结合热点相互作用。Grb2-FAT相互作用的破坏是一种预防病理性心脏肥大的治疗策略。使用Forge工具（Cresset），根据结合到FAK上的FAT的结构和静电性质产生药效基团。该药效团用作Blaze服务器（Cresset）的查询，以筛选选择性富集的4,32,508个小分子的化学文库。使用AutoDock v4，通过分层灵活对接方法进一步过滤所选化合物。使用SwissADME，MedChem Designer v.3和MOLINSPIRATION，从对接良好的化合物中，基于良好的吸附，分布，代谢，排泄和毒性（ADMET）特性选择了五种化合物。通过在水性环境中使用AMBER v15进行50 ns的模拟时间的分子动力学模拟研究，进一步证实了抑制剂的结合模式的稳定性。就药效学特征，对接分数和计算机模拟ADMET分析而言，PM2307被确定为最佳抑制剂。PM2307的计算结合亲和力优于FAT-Grb2复合物以及先前报道的小分子抑制剂。PM2307也是一种喹诺酮衍生物，与氧氟沙星药物具有相似的骨架，并具有类似药物的特性。从而，