Design of potential anti-cancer agents as COX-2 inhibitors, using 3D-QSAR modeling, molecular docking, oral bioavailability proprieties, and molecular dynamics simulation

数量结构-活动关系 分子动力学 化学 取代基 对接(动物) 立体化学 生物利用度 分子模型 计算化学 药理学 生物 医学 护理部
作者
Mohammed Er-rajy,Mohamed El fadili,Abdelmoujoud Faris,Sara Zarougui,Menana Elhallaoui
出处
期刊:Anti-Cancer Drugs [Lippincott Williams & Wilkins]
被引量:2
标识
DOI:10.1097/cad.0000000000001492
摘要

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.
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