Chtita Samir, Belhassan Assia, Bakhouch Mohamed, Taourati Abdelali Idrissi, Aouidate Adnane, Belaidi Salah, Moutaabbid Mohammed, Belaaouad Said, Bouachrine Mohammed, Lakhlifi Tahar
Laboratory of Physical Chemistry of Materials, Faculty of Sciences Ben M'Sik, Hassan II University of Casablanca, B.P. 7955, Sidi Othmane, Casablanca, Morocco.
Molecular Chemistry and Natural Substances Laboratory, Department of Chemistry, Faculty of Sciences, University Moulay Ismail, Meknes, Morocco.
Chemometr Intell Lab Syst. 2021 Mar 15;210:104266. doi: 10.1016/j.chemolab.2021.104266. Epub 2021 Feb 3.
research was executed on forty unsymmetrical aromatic disulfide derivatives as inhibitors of the SARS Coronavirus (SARS-CoV-1). Density functional theory (DFT) calculation with B3LYP functional employing 6-311 + G(d,p) basis set was used to calculate quantum chemical descriptors. Topological, physicochemical and thermodynamic parameters were calculated using ChemOffice software. The dataset was divided randomly into training and test sets consisting of 32 and 8 compounds, respectively. In attempt to explore the structural requirements for bioactives molecules with significant anti-SARS-CoV activity, we have built valid and robust statistics models using QSAR approach. Hundred linear pentavariate and quadrivariate models were established by changing training set compounds and further applied in test set to calculate predicted IC values of compounds. Both built models were individually validated internally as well as externally along with Y-Randomization according to the OECD principles for the validation of QSAR model and the model acceptance criteria of Golbraikh and Tropsha's. Model 34 is chosen with higher values of R, R and Qcv (R = 0.838, R = 0.735, Q = 0.757). It is very important to notice that anti-SARS-CoV main protease of these compounds appear to be mainly governed by five descriptors, i.e. highest occupied molecular orbital energy (E), energy of molecular orbital below HOMO energy (E), Balaban index (BI), bond length between the two sulfur atoms (S1S2) and bond length between sulfur atom and benzene ring (S2Bnz). Here the possible action mechanism of these compounds was analyzed and discussed, in particular, important structural requirements for great SARS-CoV main protease inhibitor will be by substituting disulfides with smaller size electron withdrawing groups. Based on the best proposed QSAR model, some new compounds with higher SARS-CoV inhibitors activities have been designed. Further, prediction studies on ADMET pharmacokinetics properties were conducted.
对40种不对称芳族二硫化物衍生物作为严重急性呼吸综合征冠状病毒（SARS-CoV-1）抑制剂进行了研究。采用密度泛函理论（DFT）计算，使用B3LYP泛函并采用6-311+G(d,p)基组来计算量子化学描述符。使用ChemOffice软件计算拓扑、物理化学和热力学参数。数据集被随机分为分别由32种和8种化合物组成的训练集和测试集。为了探索具有显著抗SARS-CoV活性的生物活性分子的结构要求，我们使用定量构效关系（QSAR）方法建立了有效且稳健的统计模型。通过改变训练集化合物建立了100个线性五元模型和四元模型，并进一步应用于测试集以计算化合物的预测IC值。根据经济合作与发展组织（OECD）关于QSAR模型验证的原则以及戈尔布赖赫（Golbraikh）和特罗普沙（Tropsha）的模型接受标准，对构建的两个模型分别进行了内部和外部验证以及Y-随机化。选择了R、R²和Qcv值较高的模型（R = 0.838，R² = 0.735，Qcv = 0.757）。需要注意的是，这些化合物的抗SARS-CoV主要蛋白酶似乎主要由五个描述符决定，即最高占据分子轨道能量（E）、低于HOMO能量的分子轨道能量（E）、巴拉班指数（BI）、两个硫原子之间的键长（S1S2）以及硫原子与苯环之间的键长（S2Bnz）。在此分析和讨论了这些化合物可能的作用机制，特别是对于高效SARS-CoV主要蛋白酶抑制剂的重要结构要求将是用较小尺寸的吸电子基团取代二硫化物。基于最佳提出的QSAR模型，设计了一些具有更高SARS-CoV抑制剂活性的新化合物。此外，还进行了ADMET药代动力学性质的预测研究。
