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苯磺酰胺取代的二芳基吡唑作为环氧化酶-2 抑制剂的分子见解及其结构修饰。

Molecular insights into benzene sulphonamide substituted diarylpyrazoles as cyclooxygenase-2 inhibitor and its structural modifications.

机构信息

Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRMIST, Kattankulathur, India.

Dr APJ Abdul Kalam Research Lab, SRM College of Pharmacy, SRMIST, Kattankulathur, India.

出版信息

J Biomol Struct Dyn. 2021 Sep;39(14):5093-5104. doi: 10.1080/07391102.2020.1785329. Epub 2020 Jun 30.

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 (Q)=0.5565, coefficient of determination (R)=0.6530, (R)=0.8225, cross validation leave many out (Q2)=0.5201, Concordance Correlation Coefficient (CCC)=0.7262, CCC=0.7901, and CCC=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 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

定量构效关系(QSAR)是优化先导化合物的药物设计中一种切实可行且最成功的方法之一。用 QSARINS 软件对 44 个二芳基吡唑苯磺酰胺衍生物的分子及其环氧化酶-2 抑制活性进行了 QSAR 研究。生成的显著的双描述符 QSAR 模型显示交叉验证留一法(Q)的相关系数为 0.5565、决定系数(R)为 0.6530、预测值(R)为 0.8225、交叉验证留多法(Q2)的相关系数为 0.5201、协调相关系数(CCC)为 0.7262、CCC 为 0.7901、CCC 为 0.8930。描述符 3D 基于电子衍射的结构分子表示(3D-MoRSEC-6),其中 6 是散射参数,原子电荷加权,Geary 自相关滞后 3/原子桑德森电负性加权(GATSe3)表明原子电荷和空间自相关在环氧化酶-2 抑制(COX-2)活性中起着关键作用。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其 COX-2 抑制活性。使用 Autodock 4.2.6 对最佳设计分子进行了分子对接研究,并提供了支持的吸收、分布、代谢、排泄和毒性预测。活性位点区域的残基的亲水和疏水部分都与最佳预测的活性化合物相互作用。该研究表明了对于有效的酶抑制至关重要的性质和关键相互作用,并发现该系列是进一步开发新型环氧化酶药物的有前途的先导化合物。Ramaswamy H. Sarma 通讯。

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