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Homology model of nonmuscle myosin heavy chain IIA and binding mode analysis with its inhibitor blebbistatin

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Abstract

Nonmuscle myosin heavy chain IIA (NMMHC IIA, gene code: MYH9) plays a critical role in physiological and pathological functions. A homology model of NMMHC IIA was constructed based on the crystal structure of smooth muscle myosin II. Blebbistatin, a myosin II ATPase inhibitor, had been found to bind to NMMHC IIA with Leu228 as the important amino acid residue and van der Waals contacts as the main force of the interaction. The final complex demonstrated that the destruction of the salt bridge occurred between the Arg204 and Glu427 residues when blebbistatin was present. Molecular dynamic simulation of the complex showed that the binding affinity of blebbistatin to NMMHC IIA was strongly sensitive to the nucleotide binding region and actin binding region. The disturbance of the two regions increased the enhancement of the binding cavity with blebbistatin and resulted in a slightly more expanded conformation in the nucleotide binding region and actin binding region. A combined pharmacophore- and docking-based virtual screening was performed to identify several saponins as potential inhibitors for NMMHC IIA. These findings introduce new insights on the binding mode of blebbistatin and NMMHC IIA and novel leading compounds from natural products for NMMHC IIA-related diseases.

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Acknowledgments

We acknowledge the support of this work from the laboratory of molecular design and drug discovery, China pharmaceutical university, and helpful discussions with Dr. Yadong Chen. The present research was supported by the National Key Technologies R&D Program of China (No. 2006BAI08B05-08), the Major Research Plan of the National Natural Science Foundation of China (No. 90713042), Program for New Century Excellent Talents in University (NCET-07-849), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, the Project Program of the State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. JKGZ201107), and graduate student scientific research innovation plan of jiangsu higher education institutions (CXZZ11_0795).

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Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, Department of Complex Prescription of TCM, China Pharmaceutical University, 639 Longmian Road, Nanjing, 211198, People’s Republic of China

    Yanni Lv, Junping Kou & Boyang Yu

  2. Department of Organic Chemistry, China Pharmaceutical University, Nanjing, 211198, People’s Republic of China

    Shuai Lu & Tao Lu

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  1. Yanni Lv
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  2. Shuai Lu
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  3. Tao Lu
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  4. Junping Kou
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Correspondence to Junping Kou or Boyang Yu.

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Lv, Y., Lu, S., Lu, T. et al. Homology model of nonmuscle myosin heavy chain IIA and binding mode analysis with its inhibitor blebbistatin. J Mol Model 19, 1801–1810 (2013). https://doi.org/10.1007/s00894-012-1750-3

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  • DOI: https://doi.org/10.1007/s00894-012-1750-3

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