Identify promising IKK-β inhibitors: A docking-based 3D-QSAR study combining molecular design and molecular dynamics simulation

• Published in: Arabian journal of chemistry 2022-05, Vol.15 (5), p.103786, Article 103786
• Main Authors: Li, Liang, Peng, Chang'en, Wang, Yonggang, Xiong, Chan, Liu, Yefang, Wu, Chunjie, Wang, Jiaolong
• Format: Article
• Language: English
• Subjects: 3D-QSAR; IKK-β; Molecular design; Molecular docking; Molecular dynamics simulation
• ISSN: 1878-5352; 1878-5379
• DOI: 10.1016/j.arabjc.2022.103786

Inhibitor of nuclear factor kappa B kinase subunit beta (IKK-β), a specific regulator of nuclear factor-κB (NF-κB), is considered a valid target to design novel drugs to treat rheumatoid arthritis, glomerulonephritis and various cancers. In this study, in order to design and then identify promising compounds targeting IKK-β, a series of reported IKK-β inhibitors were used to develop 3D-QSAR models. Docking-based and minimization-based poses were generated for model construction. CoMSIA model #8 based on docking poses was selected due to its satisfactory internal and external validation results and the sufficient information delivery capability. After a contour map analysis, 41 new designs were depicted based on a graphical design scheme and 25 of them were assessed as eligible for screening. Compound 21MX007 has aroused our attention for its both competitive QSAR-prediction and docking-scoring result. Detailed docking interactions of 21MX007-protein complex were investigated via a deep analysis of docking results and a comparative molecular dynamics simulation. Strong interactions and an extra hydrogen bond which echoes the H-bond requirements of substituent acquired from the design scheme were observed. From MD analysis, 21MX007-protein system was tested. The system was proved to have good stability in terms of a downward trend of RMSD and Rg values and a continuous and stable H-bond interaction and a lower average binding free energy. Thus, compound 21MX007 was successfully identified as a promising IKK-β inhibitor.