Synthesis, structural characterization, DFT calculations, molecular docking, and molecular dynamics simulations of a novel ferrocene derivative to unravel its potential antitumor activity

In this article, we describe a set of subsequent five-steps chemical reactions to synthesize a ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (<b>compound 10</b>). Structural characterization of <b>10</b> and its intermediate products was also performed and reported to attest to their formation. A molecular docking study was performed to propose the novel synthesized ferrocene derivative (<b>10</b>) as a potential antitumor candidate targeting the mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1. The computed docking score of (<b>10</b>) at −9.50 kcal/mol compared to the native anticancer staurosporine at −8.72 kcal/mol postulated a promising anticancer activity. Also, molecular dynamics (MD) simulations were carried out for 500 ns followed by MM-GBSA-binding free energy calculations for both the docked complexes of ferrocene and staurosporine to give more deep insights into their dynamic behavior in physiological conditions. Furthermore, DFT calculations were performed to unravel some of the physiochemical characteristics of the ferrocene derivative (<b>10</b>). The quantum mechanics calculations shed the light on some of the structural and electrochemical configurations of (<b>10</b>) which would open the horizon for further investigation. HighlightsThe synthesis of a ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (<b>compound 10</b>) was described.Structural characterizations of ferrocene derivative (<b>10</b>) and its intermediate products were also performed.DFT calculations, molecular docking, molecular dynamics, and MM-GBSA calculations were carried out.Computational studies revealed the antitumor potential of ferrocene derivative (<b>10</b>) through targeting and inhibiting mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1. The synthesis of a ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (<b>compound 10</b>) was described. Structural characterizations of ferrocene derivative (<b>10</b>) and its intermediate products were also performed. DFT calculations, molecular docking, molecular dynamics, and MM-GBSA calculations were carried out. Computational studies revealed the antitumor potential of ferrocene derivative (<b>10</b>) through targeting and inhibiting mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1. Communicated by Ramaswamy H. Sarma

本文报道了一套五步连续化学反应路线，用于合成一种二茂铁衍生物 (ferrocene derivative)，其系统命名为1-(5-(二苯基膦基)环戊-1,3-二烯-1-基)乙基)亚氨基)-1,3-二氢异苯并呋喃-5-基)甲醇，即化合物10。本研究还对化合物10及其各中间体产物进行了结构表征，并通过表征结果证实了其成功合成。
本研究通过分子对接 (molecular docking) 实验，将该新型合成的二茂铁衍生物（化合物10）开发为靶向丝裂原活化蛋白（MAP）激酶相互作用激酶（Mnk）1的潜在抗肿瘤候选药物。化合物10的计算对接得分为-9.50 kcal/mol，而天然抗肿瘤药物星形孢菌素（staurosporine）的对接得分为-8.72 kcal/mol，这表明该化合物具有良好的抗肿瘤活性潜力。
此外，本研究对二茂铁衍生物与星形孢菌素的对接复合物分别开展了500 ns的分子动力学 (molecular dynamics, MD) 模拟，并随后进行了MM-GBSA结合自由能计算，以深入探究二者在生理条件下的动态行为。
此外，本研究还通过密度泛函理论 (Density Functional Theory, DFT) 计算，解析了化合物10的部分理化性质。该量子力学计算揭示了化合物10的部分结构与电化学构型特征，为后续相关研究拓展了方向。
研究亮点：
1. 报道了一种二茂铁衍生物的合成路线，该化合物系统命名为1-(5-(二苯基膦基)环戊-1,3-二烯-1-基)乙基)亚氨基)-1,3-二氢异苯并呋喃-5-基)甲醇（即化合物10）；
2. 对化合物10及其中间体产物进行了结构表征；
3. 开展了密度泛函理论（DFT）计算、分子对接、分子动力学模拟以及MM-GBSA结合自由能计算；
4. 计算研究表明，化合物10可通过靶向并抑制丝裂原活化蛋白（MAP）激酶相互作用激酶（Mnk）1，从而发挥抗肿瘤潜力。
本研究再次报道了上述二茂铁衍生物（化合物10）的合成路线，并对其及中间体产物进行结构表征，开展了密度泛函理论计算、分子对接、分子动力学模拟及MM-GBSA结合自由能计算，证实其可通过靶向抑制丝裂原活化蛋白（MAP）激酶相互作用激酶（Mnk）1发挥抗肿瘤潜力。本文由Ramaswamy H. Sarma通讯。