Designing of the N-ethyl-4-(pyridin-4-yl)benzamide based potent ROCK1 inhibitors using docking, molecular dynamics, and 3D-QSAR

PeerJ

article

Suparna Ghosh¹  Seketoulie Keretsu¹  Seung Joo Cho¹ 

[1] Department of Biomedical Sciences, College of Medicine, Chosun University;Department of Cellular and Molecular Medicine, College of Medicine, Chosun University

关键词: Rho-associated kinase-1 (ROCK1);    Cardio-vascular disease;    Molecular docking;    Molecular dynamics;    MMPBSA;    3D-QSAR;    CoMFA;    CoMSIA;    ADME/Tox;   

DOI  :  10.7717/peerj.11951

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

Rho-associated kinase-1 (ROCK1) has been recognized for its pivotal role in heart diseases, different types of malignancy, and many neurological disorders. Hyperactivity of ROCK phosphorylates the protein kinase-C (PKC), which ultimately induces smooth muscle cell contraction in the vascular system. Inhibition of ROCK1 has been shown to be a promising therapy for patients with cardiovascular disease. In this study, we have conducted molecular modeling techniques such as docking, molecular dynamics (MD), and 3-Dimensional structure-activity relationship (3D-QSAR) on a series of N-ethyl-4-(pyridin-4-yl)benzamide-based compounds. Docking and MD showed critical interactions and binding affinities between ROCK1 and its inhibitors. To establish the structure-activity relationship (SAR) of the compounds, 3D-QSAR techniques such as Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were used. The CoMFA (q2 = 0.774, r2 = 0.965, ONC = 6, and rpred2= 0.703) and CoMSIA (q2 = 0.676, r2 = 0.949, ONC = 6, and rpred2= 0.548) both models have shown reasonable external predictive activity, and contour maps revealed favorable and unfavorable substitutions for chemical group modifications. Based on the contour maps, we have designed forty new compounds, among which, seven compounds exhibited higher predictive activity (pIC50). Further, we conducted the MD study, ADME/Tox, and SA score prediction using the seven newly designed compounds. The combination of docking, MD, and 3D-QSAR studies helps to understand the coherence modification of existing molecules. Our study may provide valuable insight into the development of more potent ROCK1 inhibitors.

【 授权许可】

CC BY