Modeling the structural properties of novel morpholine-bearing 1, 5-diaryl-diazole derivatives as potent COX-2 inhibitor, two proposed models based on CoMFA and CoMSIA were evaluated by external and internal validation methods. Partial least squares analysis produced statistically significant models with Q 2 values of 0.668 and 0.652 for CoMFA and CoMSIA, respectively, and also a significant non-validated correlation coefficient R² with values of 0.882 and 0.878 for CoMFA and CoMSIA, respectively. Both models met the requirements of Golbraikh and Tropsha, which means that both models are consistent with all validation techniques. Analysis of the CoMFA and CoMSIA contribution maps and molecular docking revealed that the R1 substituent has a very significant effect on their biological activity. The most active molecules were evaluated for their thermodynamic stability by performing MD simulations for 100 ns; it was revealed that the designed macromolecular ligand complex with 3LN1 protein exhibits a high degree of structural and conformational stability. Based on these results, we predicted newly designed compounds, which have acceptable oral bioavailability properties and would have high synthetic accessibility.

中文翻译：

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使用 3D-QSAR 建模、分子对接、口服生物利用度特性和分子动力学模拟设计潜在的抗癌药物 COX-2 抑制剂。

对新型含吗啉的 1, 5-二芳基二唑衍生物作为有效 COX-2 抑制剂的结构特性进行建模，通过外部和内部验证方法对基于 CoMFA 和 CoMSIA 的两个提出的模型进行了评估。偏最小二乘分析产生了统计上显着的模型，CoMFA 和 CoMSIA 的 Q 2 值分别为 0.668 和 0.652，并且还产生了显着的未验证相关系数 R²，CoMFA 和 CoMSIA 的值分别为 0.882 和 0.878。这两个模型都满足 Golbraikh 和 Tropsha 的要求，这意味着这两个模型与所有验证技术都是一致的。CoMFA和CoMSIA贡献图和分子对接分析表明，R1取代基对其生物活性有非常显着的影响。通过执行 100 ns 的 MD 模拟来评估最活跃分子的热力学稳定性；结果表明，设计的与3LN1蛋白的大分子配体复合物表现出高度的结构和构象稳定性。基于这些结果，我们预测新设计的化合物具有可接受的口服生物利用度特性，并且具有较高的合成可及性。