Daoui Ossama, Elkhattabi Souad, Chtita Samir, Elkhalabi Rachida, Zgou Hsaine, Benjelloun Adil Touimi
Laboratory of Engineering, Systems and Applications, National School of Applied Sciences, Sidi Mohamed Ben Abdellah-Fez University, Fez, Morocco.
Laboratory of Physical Chemistry of Materials, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, Casablanca P.O. Box 7955, Morocco.
Heliyon. 2021 Jul 3;7(7):e07463. doi: 10.1016/j.heliyon.2021.e07463. eCollection 2021 Jul.
A quantitative structure-activity relationship (QSAR) study is performed on 48 novel 4,5,6,7-tetrahydrobenzo[D]-thiazol-2 derivatives as anticancer agents capable of inhibiting c-Met receptor tyrosine kinase. The present study is conducted using multiple linear regression, multiple nonlinear regression and artificial neural networks. Three QSAR models are developed after partitioning the database into two sets (training and test) via the k-means method. The obtained values of the correlation coefficients by the three developed QSAR models are 0.90, 0.91 and 0.92, respectively. The resulting models are validated by using the external validation, leave-one-out cross-validation, Y-randomization test, and applicability domain methods. Moreover, we evaluated the drug-likeness properties of seven selected molecules based on their observed high activity to inhibit the c-Met receptor. The results of the evaluation showed that three of the seven compounds present drug-like characteristics. In order to identify the important active sites for the inhibition of the c-Met receptor responsible for the development of cancer cell lines, the crystallized form of the Crizotinib-c-Met complex (PDB code: 2WGJ) is used. These sites are used as references in the molecular docking test of the three selected molecules to identify the most suitable molecule for use as a new c-Met inhibitor. A comparative study is conducted based on the evaluation of the predicted properties of ADMET between the candidate molecule and the Crizotinib inhibitor. The comparison results show that the selected molecule can be used as new anticancer drug candidates.
对48种新型4,5,6,7-四氢苯并[D]-噻唑-2衍生物作为能够抑制c-Met受体酪氨酸激酶的抗癌剂进行了定量构效关系(QSAR)研究。本研究采用多元线性回归、多元非线性回归和人工神经网络进行。通过k均值法将数据库划分为两组(训练集和测试集)后,建立了三个QSAR模型。三个开发的QSAR模型得到的相关系数值分别为0.90、0.91和0.92。通过外部验证、留一法交叉验证、Y随机化检验和适用域方法对所得模型进行了验证。此外,我们基于观察到的七种选定分子对c-Met受体的高抑制活性,评估了它们的类药性质。评估结果表明,七种化合物中有三种具有类药特性。为了确定抑制c-Met受体从而导致癌细胞系发展的重要活性位点,使用了克唑替尼-c-Met复合物的结晶形式(PDB代码:2WGJ)。这些位点在三种选定分子的分子对接试验中用作参考,以确定最适合用作新型c-Met抑制剂的分子。基于对候选分子与克唑替尼抑制剂之间ADMET预测性质的评估进行了比较研究。比较结果表明,所选分子可作为新型抗癌药物候选物。