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A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors
Department of Materials Science and Chemical Engineering, Dalian University of Technology, Dalian 116023, China
Department of Ophthalmology, Qi Lu Hospital, Medical School of Shandong University, Jinan 250012, China
Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
College of Chemistry and Chemical Engineering, Graduate School of the Chinese Academy of Sciences, Beijing 100049, China
Institute for Computational Science and Engineering, Laboratory of New Fibrous Materials and Modern Textile, The Growing Base for State Key Laboratory, Qingdao University, Qingdao 266071, China
Department of Chemistry, Lanzhou University, Lanzhou 730000, China
* Authors to whom correspondence should be addressed.
Received: 23 April 2012; in revised form: 25 May 2012 / Accepted: 28 May 2012 / Published: 8 June 2012
Abstract: Mitogen-activated protein kinase-activated protein kinase 2 (MK-2) has been identified as a drug target for the treatment of inflammatory diseases. Currently, a series of thiourea analogs as potent MK-2 inhibitors were studied using comprehensive computational methods by 3D-QSAR, molecular docking and molecular dynamics simulations for a further improvement in activities. The optimal 3D models exhibit high statistical significance of the results, especially for the CoMFA results with r2ncv, q2 values of 0.974, 0.536 for the internal validation, and r2pred, r2m values of 0.910, 0.723 for the external validation and Roy’s index, respectively. In addition, more rigorous validation criteria suggested by Tropsha were also employed to check the built models. Graphic representation of the results, as contoured 3D coefficient plots, also provides a clue to the reasonable modification of molecules: (i) The substituent with a bulky size and electron-rich group at the C5 position of the pyrazine ring is required to enhance the potency; (ii) The H-bond acceptor group in the C3 position of the pyrazine ring is likely to be helpful to increase MK-2 inhibition; (iii) The small and electropositive substituent as a hydrogen bond donor of the C2 position in the oxazolone ring is favored; In addition, several important amino acid residues were also identified as playing an important role in MK-2 inhibition. The agreement between 3D-QSAR, molecular docking and molecular dynamics simulations also proves the rationality of the developed models. These results, we hope, may be helpful in designing novel and potential MK-2 inhibitors.
Keywords: 3D-QSAR; molecular dynamics; MK-2 inhibitors; CoMFA; CoMSIA
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MDPI and ACS Style
Hao, M.; Ren, H.; Luo, F.; Zhang, S.; Qiu, J.; Ji, M.; Si, H.; Li, G. A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors. Int. J. Mol. Sci. 2012, 13, 7057-7079.
Hao M, Ren H, Luo F, Zhang S, Qiu J, Ji M, Si H, Li G. A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors. International Journal of Molecular Sciences. 2012; 13(6):7057-7079.
Hao, Ming; Ren, Hong; Luo, Fang; Zhang, Shuwei; Qiu, Jieshan; Ji, Mingjuan; Si, Hongzong; Li, Guohui. 2012. "A Computational Study on Thiourea Analogs as Potent MK-2 Inhibitors." Int. J. Mol. Sci. 13, no. 6: 7057-7079.