Chaube Udit, Chhatbar Dhara, Bhatt Hardik
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, S.G. Highway, Chharodi, Ahmedabad 382 481, India.
Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, S.G. Highway, Chharodi, Ahmedabad 382 481, India.
Bioorg Med Chem Lett. 2016 Feb 1;26(3):864-874. doi: 10.1016/j.bmcl.2015.12.075. Epub 2015 Dec 23.
According to WHO statistics, lung cancer is one of the leading causes of death among all other types of cancer. Many genes get mutated in lung cancer but involvement of EGFR and KRAS are more common. Unavailability of drugs or resistance to the available drugs is the major problem in the treatment of lung cancer. In the present research, mTOR was selected as an alternative target for the treatment of lung cancer which involves PI3K/AKT/mTOR pathway. 28 synthetic mTOR inhibitors were selected from the literature. Ligand based approach (CoMFA and CoMSIA) and structure based approach (molecular dynamics simulations assisted molecular docking study) were applied for the identification of important features of benzoxazepine moiety, responsible for mTOR inhibition. Three different alignments were tried to obtain best QSAR model, of which, distil was found to be the best method, as it gave good statistical results. In CoMFA, Leave One Out (LOO) cross validated coefficients (q(2)), conventional coefficient (r(2)) and predicted correlation coefficient (r(2)pred) values were found to be 0.615, 0.990 and 0.930, respectively. Similarly in CoMSIA, q(2), r(2)ncv and r(2)pred values were found to be 0.748, 0.986 and 0.933, respectively. Molecular dynamics and simulations study revealed that B-chain of mTOR protein was stable at and above 500 FS with respect to temperature (at and above 298 K), Potential energy (at and above 7669.72 kJ/mol) and kinetic energy (at and above 4009.77 kJ/mol). Molecular docking study was performed on simulated protein of mTOR which helped to correlate interactions of amino acids surrounded to the ligand with contour maps generated by QSAR method. Important features of benzoxazepine were identified by contour maps and molecular docking study which would be useful to design novel molecules as mTOR inhibitors for the treatment of lung cancer.
根据世界卫生组织的统计数据，肺癌是所有其他类型癌症中主要的致死原因之一。肺癌中有许多基因发生突变，但表皮生长因子受体（EGFR）和 Kirsten 大鼠肉瘤病毒原癌基因（KRAS）的参与更为常见。药物的不可用性或对现有药物的耐药性是肺癌治疗中的主要问题。在本研究中，哺乳动物雷帕霉素靶蛋白（mTOR）被选为肺癌治疗的替代靶点，其涉及磷脂酰肌醇-3-激酶（PI3K）/蛋白激酶 B（AKT）/mTOR 信号通路。从文献中挑选了 28 种合成的 mTOR 抑制剂。基于配体的方法（比较分子场分析法（CoMFA）和比较分子相似性指数分析法（CoMSIA））以及基于结构的方法（分子动力学模拟辅助分子对接研究）被用于确定苯并恶唑嗪部分负责 mTOR 抑制作用的重要特征。尝试了三种不同的比对方式以获得最佳的定量构效关系（QSAR）模型，其中，蒸馏法被发现是最佳方法，因为它给出了良好的统计结果。在 CoMFA 中，留一法（LOO）交叉验证系数（q(2)）、常规系数（r(2)）和预测相关系数（r(2)pred）值分别为 0.615、0.990 和 0.930。同样，在 CoMSIA 中，q(2)、r(2)ncv 和 r(2)pred 值分别为 0.748、0.986 和 0.933。分子动力学和模拟研究表明，mTOR 蛋白的 B 链在温度（298K 及以上）、势能（7669.72kJ/mol 及以上）和动能（4009.77kJ/mol 及以上）方面，在 500 飞秒及以上时是稳定的。对 mTOR 的模拟蛋白进行了分子对接研究，这有助于将围绕配体的氨基酸相互作用与通过 QSAR 方法生成的等高线图相关联。通过等高线图和分子对接研究确定了苯并恶唑嗪的重要特征，这将有助于设计新型分子作为 mTOR 抑制剂用于肺癌治疗。
