Abstract

The protein–protein interactions (PPIs) in the biological systems are important to maintain a number of cellular processes. Several disorders including cancer may be developed due to dysfunction in the assembly of PPI networks. Hence, targeting intracellular PPIs can be considered as a crucial drug target for cancer therapy. Among the enormous and diverse group of cancer-enabling PPIs, the Hsp90–Cdc37 is prominent for cancer therapeutic development. The successful inhibition of Hsp90–Cdc37 PPI interface can be an important therapeutic option for cancer management. In the current study, a set of more than sixty thousand compounds belong to four databases were screened through a multi-steps molecular docking study in Glide against the Hsp90–Cdc37 interaction interface. The Glide-score and Prime-MM-GBSA based binding free energy of DCZ3112, standard Hsp90–Cdc37 inhibitor were found to be −6.96 and −40.46 kcal/mol, respectively. The above two parameters were used as cut-off score to reduce the chemical space from all successfully docked molecules. Furthermore, the in-silico pharmacokinetics parameters, common-feature pharmacophore analyses and the molecular binding interactions were used to wipe out the inactive molecules. Finally, four molecules were found to be important to modulate the Hsp90–Cdc37 interface. The potentiality of the final four molecules was checked through several drug-likeness characteristics. The molecular dynamics (MD) simulation study explained that all four molecules retained inside the interface of Hsp90–Cdc37. The binding free energy of each molecule obtained from the MD simulation trajectory was clearly explained the strong affection towards the Hsp90–Cdc37. Hence, the proposed molecule might be crucial for successful inhibition of the Hsp90–Cdc37 interface.

Communicated by Ramaswamy H. Sarma

摘要

生物系统中的蛋白质-蛋白质相互作用 (PPI) 对于维持许多细胞过程很重要。由于 PPI 网络组装中的功能障碍，可能会出现包括癌症在内的几种疾病。因此，靶向细胞内 PPI 可以被认为是癌症治疗的关键药物靶点。在庞大而多样的致癌 PPI 组中，Hsp90-Cdc37 在癌症治疗发展中非常突出。成功抑制 Hsp90–Cdc37 PPI 界面可能是癌症管理的重要治疗选择。在目前的研究中，通过 Glide 中针对 Hsp90-Cdc37 相互作用界面的多步骤分子对接研究，筛选了一组属于四个数据库的六万多种化合物。DCZ3112 基于 Glide-score 和 Prime-MM-GBSA 的结合自由能，发现标准 Hsp90–Cdc37 抑制剂分别为 -6.96 和 -40.46 kcal/mol。上述两个参数被用作截止分数，以减少所有成功对接分子的化学空间。此外，该使用计算机内药代动力学参数、共同特征药效团分析和分子结合相互作用来消除非活性分子。最后，发现四种分子对调节 Hsp90-Cdc37 界面很重要。最后四个分子的潜力是通过几个药物相似性特征来检查的。分子动力学 (MD) 模拟研究解释说，所有四种分子都保留在 Hsp90-Cdc37 的界面内。从 MD 模拟轨迹获得的每个分子的结合自由能清楚地解释了对 Hsp90-Cdc37 的强烈影响。因此，所提出的分子可能对成功抑制 Hsp90-Cdc37 界面至关重要。

由 Ramaswamy H. Sarma 传达