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European Pharmaceutical Students’ Association
Molecular modeling of RHO kinase 1 inhibitors using quantitative structure-activity analysis Author: Jelena Rebić Scientific Coordinator: Milica Radan, Mpharm; Teodora Djikić, PhD Institution: Department of Pharmaceutical chemistry, Faculty of Pharmacy University of Belgrad
INTRODUCTION: In addition to the regulatory role in actin and myosin function, rho-associated protein kinase (ROCK) influences the processes of proliferation, differentiation, apoptosis and oncogenic transmission. Therefore, alterations in their activity are associated with various pathological states including cardiovascular and neurodegenerative diseases, glaucoma, Raynaud’s disease, or erectile dysfunction. This study enables us to gain deeper insights into the structural requirements of studied compounds that affect ROCK1 activity. AIM: Develop a robust 3D-quantitative structure-activity relationship (3D-QSAR) model with good predictive power that could be used for pharmacophore analysis of studied inhibitors. MATERIALS AND METHODS: The 3D-QSAR study was performed on 48 compounds structurally comprising pyridine derivatives and oxadiazole derivatives. Optimized compounds were divided into two groups, a training set with 34 compounds, and a test set with 14 compounds. RESULTS: The calculated statistical parameters of internal (R2=0,920; Q2=0,760) and external (R2pred=0,746; r2m, r/2m, >0,5; ∆r2m<0,2) validations indicated good predictive power of the created model and the possibility of its application for pharmacophore analysis of the studied ROCK1 kinase inhibitors. CONCLUSION: Based on the results of our study, we may conclude that, the higher activity of pyridine derivatives is due to the presence of two heterocyclic groups at the optimal distance described by the positive variables var28 (DRY-DRY: 11.20-11.60Å), var208 (TYP-TYP: 14, 80-15,20Å) and var383 (DRY-TYP: 16.40-16.80Å). These variables are not present, or are weakly expressed in
the second group of compounds. Analysis of variables with a negative influence showed that the presence of two steric hot spots, at a longer distance, var217 (TYP-TYP: 18.4018.80Å), significantly reduces the activity of pyridine derivatives. Variables var424 (O-N1: 10.00-10.40Å) and var477 (O-TYP: 8, 408.80Å) which represent distance between hydrogen bond donor and acceptor, or hydrogen bond donor and steric hot spot, respectively, also had negative influence on the activity.
