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Year: 2013 Volume: 9 Issue: 2

Year: 2013 Volume: 9 Issue: 1

Discovery and optimization of triazine derivatives as ROCK1 inhibitors: molecular docking, molecular dynamics simulations and free energy calculations.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Shen, Mingyun Zhou, Shunye Li, Youyong Pan, Peichen Zhang, Liling Hou, Tingjun
Description	Country affiliation: China Author Affiliation: Shen M ( Institute of Functional Nano & Soft Materials (FUNSOM) and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China.)
Abstract	Rho-associated protein kinases (ROCK1 and ROCK2) are promising targets for a number of diseases, including cardiovascular disorders, nervous system diseases, cancers, etc. Recently, we have successfully identified a ROCK1 inhibitor (1) with the triazine core. In order to gain a deeper insight into the microscopic binding of this inhibitor with ROCK1 and design derivatives with improved potency, the interactions between ROCK1 and a series of triazine/pyrimidine-based inhibitors were studied by using an integrated computational protocol that combines molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and binding energy decomposition analysis. First, three docking protocols, rigid receptor docking, induced fit docking, QM-polarized ligand docking, were used to determine the binding modes of the studied inhibitors in the active site of ROCK1. The results illustrate that rigid receptor docking achieves the best performance to rank the binding affinities of the studied inhibitors. Then, based on the predicted structures from molecular docking, MD simulations and MM/GBSA free energy calculations were employed to determine the dynamic binding process and compare the binding modes of the inhibitors with different activities. The binding free energies predicted by MM/GBSA are in good agreement with the experimental bioactivities, and the analysis of the individual energy terms suggests that the van der Waals interaction is the major driving force for ligand binding. In addition, the residue-inhibitor interaction spectra were obtained by the MM/GBSA free energy decomposition analysis, and the important residues for achieving strong binding were highlighted, which affords important guidance for the rational design of novel ROCK inhibitors. Finally, a variety of derivatives of inhibitor 1 were designed and four of them showed promising potency according to the predictions. We expect that our study can provide significant insight into the development of improved inhibitors of ROCK1.
File Format	HTM / HTML
ISSN	1742206X
Issue Number	3
Volume Number	9
e-ISSN	17422051
Journal	Molecular BioSystems
Language	English
Publisher	Royal Society of Chemistry
Publisher Date	2013-03-01
Publisher Place	Great Britain (UK)
Access Restriction	Subscribed
Subject Keyword	Discipline Molecular Biology Discipline Biochemistry Molecular Docking Simulation Molecular Dynamics Simulation Protein Kinase Inhibitors Chemistry Rho-associated Kinases Antagonists & Inhibitors Amino Acid Motifs Catalytic Domain Cell Line, Tumor Drug Discovery Humans Hydrogen Bonding Hydrophobic And Hydrophilic Interactions Protein Binding Pyrimidines Thermodynamics Triazines Journal Article Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject Domain (in MeSH)	Cells Eukaryota Heterocyclic Compounds Enzymes and Coenzymes Chemical Actions and Uses Investigative Techniques Physical Phenomena Chemical Phenomena

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