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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Identification of selective MMP-9 inhibitors through multiple e-pharmacophore, ligand-based pharmacophore, molecular docking, and density functional theory approaches
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Identification of selective MMP-9 inhibitors through multiple e-pharmacophore, ligand-based pharmacophore, molecular docking, and density functional theory approaches

机译：通过多种电子药物，配体的药仔，分子对接和密度泛函理论方法鉴定选择性MMP-9抑制剂

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Matrix metalloproteinase-9 (MMP-9) is a significant target for the development of drugs for the treatment of arthritis, CNS disorders, and cancer metastasis. The structure-based and ligand-based methods were used for the virtual screening (VS) of database compounds to obtain potent and selective MMP-9 inhibitors. Experimentally known MMP-9 inhibitors were used to grow up ligand-based three pharmacophore models utilizing Schrodinger suite. The X-ray crystallographic structures of MMP-9 with different inhibitors were used to develop five energy-optimized structure-based (e-pharmacophore) models. All developed pharmacophores were validated and applied to screen the Zinc database. Pharmacophore matched compounds were subjected to molecular docking to retrieve hits with novel scaffolds. The molecules with diverse structures, high docking scores and low binding energies for various crystal structures of MMP-9, were selected as final hits. The Induced fit docking (IFD) analysis provided significant information about the driving of inhibitor to approve a suitable bioactive conformational position in the active site of protein. Since charge transfer reaction occurs during receptor-ligand interaction, therefore, electronic features of hits (ligands) are interesting parameters to explain the binding interactions. Density functional theory (DFT) at B3LYP/6-31G* level was utilized to explore electronic features of hits. The docking study of hits using AutoDock was helpful to establish the binding interactions. The study illustrates that the combined pharmacophore approach is advantageous to identify diverse hits which have better binding affinity to the active site of the enzyme for all possible bioactive conformations. The approach used in the study is worthy to design drugs for other targets.
机译：基质金属蛋白酶-9（MMP-9）是用于治疗关节炎，CNS疾病和癌症转移的药物的显着靶标。基于结构的和基于配体的方法用于数据库化合物的虚拟筛选（Vs），以获得有效和选择性MMP-9抑制剂。通过Schrodinger套件使用实验已知的MMP-9抑制剂来培养基于配体的三种药物光线模型。使用不同抑制剂的MMP-9的X射线晶形结构用于开发五种能量优化的基于结构（E-药物）模型。验证所有开发的药效线并施用以筛选锌数据库。对药物团相匹配的化合物进行分子对接以用新颖的支架检索击球。选择具有不同结构，高对接分数和用于各种晶体结构的MMP-9的晶体结构的分子作为最终命中。诱导的配合对接（IFD）分析提供了有关抑制剂驱动的重要信息，以批准蛋白质活性位点中的合适的生物活性构象位置。由于在受体 - 配体相互作用期间发生电荷转移反应，因此，击中（配体）的电子特征是有趣的参数来解释结合相互作用。 B3LYP / 6-31G *级别的密度泛函理论（DFT）用于探索点击的电子特征。使用Autodock的命中的对接研究有助于建立结合相互作用。该研究表明，组合的药疗法方法是有利的，鉴定不同的次数，这对于所有可能的生物活性构象具有更好的对酶的活性位点具有更好的结合亲和力。该研究中使用的方法是值得为其他目标设计药物。

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