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.

Questions & answers

Please, tell us a little bit more about yourself. My name is Jelena Rebic and I am currently in my final year of studies at the Faculty of Pharmacy, University of Belgrade, Serbia. This is my first time that I apply for ESSP and I am thrilled to be accepted. In my freetime I tend to travel, go out and dance Serbian national dance.

Tell us a bit more about your research and its significance. Inhibitors of ROCK1 are being developed nowadays, but still there are a lot of possibilities in its research, structure development and activity. Specifically, 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 kinase activity.

What was the biggest challenge while carrying out the research and how did you overcome that? In my case, I was having troubles with mastering the programs for energy optimisation such as Gaussian and later for 3D-QSAR, Pentacle. Later on, as I trained and learnt about these systems, the most challenging was finding the best model. There were, I think, at least 30 models that I made until together with my mentor we selected the best one, with the most optimised activity and parameters of internal and external validation. In your opinion, what is the benefit of joining ESSP and what advice do you have for students undertaking research in the future? In my opinion every student that starts a research project should be courageous enough to apply for ESSP. In my case, I have done three research papers so far, and I can say it is a very challenging task. But if you are persistent and with the help from your mentor, you can really achieve anything. Having a laboratory or theoretical experience outside the regular faculty program, is an unique experience from which you can learn a lot about science and moreover, about yourself.