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.
J Mol Model. 2013 Apr;19(4):1801-10. doi: 10.1007/s00894-012-1750-3. Epub 2013 Jan 13.
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.
非肌肉肌球蛋白重链 IIA（NMMHC IIA，基因编码：MYH9）在生理和病理功能中起着关键作用。基于平滑肌肌球蛋白的晶体结构，构建了 NMMHC IIA 的同源模型。肌球蛋白 II ATP 酶抑制剂 blebbistatin 已被发现与 NMMHC IIA 结合，亮氨酸 228 是重要的氨基酸残基，范德华力接触是相互作用的主要力。最终的复合物表明，当 blebbistatin 存在时，Arg204 和 Glu427 残基之间的盐桥被破坏。复合物的分子动力学模拟表明，blebbistatin 与 NMMHC IIA 的结合亲和力对核苷酸结合区和肌动蛋白结合区非常敏感。两个区域的干扰增加了与 blebbistatin 的结合腔的增强，导致核苷酸结合区和肌动蛋白结合区的构象略微扩展。进行了基于药效团和对接的虚拟筛选，以鉴定几种皂苷作为 NMMHC IIA 的潜在抑制剂。这些发现为 blebbistatin 与 NMMHC IIA 的结合模式以及天然产物中用于 NMMHC IIA 相关疾病的新型先导化合物提供了新的见解。
