Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Mol Divers. 2018 May;22(2):383-395. doi: 10.1007/s11030-017-9804-1. Epub 2018 Feb 8.
MMP-12 belongs to a large family of proteases called matrix metalloproteinases (MMPs) that degrades elastin. The main pathologic role of MMP-12 overexpression was suggested to be associated with pathogenesis mechanism of inflammatory respiratory diseases and atherosclerosis. An integrated ligand- and structure-based virtual screening was employed in hope of finding inhibitors with new scaffolds and selectivity for MMP-12. Seven compounds among 18 experimentally tested compounds had a measurable effect on the inhibition of MMP-12 enzyme. Our results demonstrated the applicability of the developed pharmacophore model and selected crystal structure (PDB code: 3F17) to discover new MMP-12 inhibitors. The receptor structure was selected based on cross-docking results. Here, we report the discovery of new class of MMP-12 inhibitors that could be used for lead optimization. For the inhibition of MMP-12, the significance of its interactions with the catalytic residues Glu219 and Ala182 was emphasized through the inspection of the docking poses.
MMP-12 属于基质金属蛋白酶 (MMPs) 大家族，能够降解弹性蛋白。MMP-12 过表达的主要病理作用被认为与炎症性呼吸道疾病和动脉粥样硬化的发病机制有关。本研究采用基于配体和结构的整合虚拟筛选方法，以期找到具有新型骨架和对 MMP-12 选择性的抑制剂。在 18 种经过实验测试的化合物中，有 7 种化合物对 MMP-12 酶的抑制具有可衡量的作用。我们的研究结果表明，所开发的药效团模型和所选的晶体结构（PDB 代码：3F17）适用于发现新的 MMP-12 抑制剂。受体结构是根据对接结果选择的。在这里，我们报告了一类新的 MMP-12 抑制剂的发现，可用于优化先导化合物。通过对接构象的检查，强调了 MMP-12 与催化残基 Glu219 和 Ala182 的相互作用对其抑制作用的重要性。
