Abstract

Quantitative Structure Activity Relationship (QSAR) is one of the realistic and most successful methods for drug design in optimizing a lead. A series of forty-four molecules from diarylpyrazole benzene sulphonamide derivatives with their cyclooxygenase-2 inhibitory activity were subjected to qsar studies using QSARINS software. The significant two descriptor qsar model generated showed correlation coefficient of cross validation leave one out (Q²_LOO)=0.5565, coefficient of determination (R²)=0.6530, (R²_ext)=0.8225, cross validation leave many out (Q2_LMO)=0.5201, Concordance Correlation Coefficient (CCC_cv)=0.7262, CCC_tr=0.7901, and CCC_ext=0.8930. The descriptor 3D Molecular Representations of Structures based on Electronic diffraction (3D-MoRSEC-6) weighted by atomic charges, where 6 is scattering parameter and Geary Autocorrelation-lag3/weighted by atomic Sanderson electronegativities (GATSe3) revealed that the atomic charges and spatial autocorrelation play a key role in Cyclooxygenase-2 inhibitory (COX-2) activity. New lead molecules were designed based on key structural findings and predicted for their COX-2 inhibitory activity using the developed two-descriptor model. Molecular docking studies were carried out for the best-designed molecules using Autodock 4.2.6 along with supportive in silico absorption, distribution, metabolism, excretion, and toxicity predictions. Both the hydrophilic as well as hydrophobic parts of the residues of active site regions interacted with best predicted active compounds. The study suggests crucial properties and key interactions that are essential for potent enzyme inhibition and finds this series as a promising lead for further development as novel cyclooxygenase agents.

Communicated by Ramaswamy H. Sarma

摘要

定量结构活性关系 (QSAR) 是药物设计中优化先导药物的现实和最成功的方法之一。使用 QSARINS 软件对来自二芳基吡唑苯磺酰胺衍生物的一系列 44 个具有环加氧酶 2 抑制活性的分子进行了 qsar 研究。生成的显着两个描述符 qsar 模型显示交叉验证留一相关系数 (Q ² _LOO )=0.5565，决定系数 (R ² )=0.6530，(R ² _ext )=0.8225，交叉验证留多（Q2 _LMO） )=0.5201, 一致性相关系数 (CCC _cv )=0.7262, CCC _tr =0.7901, 和 CCC _ext=0.8930。基于原子电荷加权的电子衍射 (3D-MoRSEC-6) 的描述符 3D 分子表示结构，其中 6 是散射参数，Geary Autocorrelation-lag3/由原子 Sanderson 电负性 (GATSe3) 加权显示原子电荷和空间自相关在 Cyclooxygenase-2 抑制 (COX-2) 活性中起关键作用。基于关键结构发现设计了新的先导分子，并使用开发的双描述符模型预测了它们的 COX-2 抑制活性。使用 Autodock 4.2.6 以及支持的in silico对设计最佳的分子进行了分子对接研究吸收、分布、代谢、排泄和毒性预测。活性位点区域残基的亲水部分和疏水部分都与最佳预测的活性化合物相互作用。该研究提出了对有效酶抑制至关重要的关键特性和关键相互作用，并发现该系列是进一步开发作为新型环氧合酶剂的有希望的先导。

由 Ramaswamy H. Sarma 交流