Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Aichi, Japan.
J Mol Graph Model. 2012 Mar;33:1-11. doi: 10.1016/j.jmgm.2011.10.006. Epub 2011 Nov 2.
Biochemical functions of the metalloprotease thermolysin (TLN) are controlled by various inhibitors. In a recent study we identified 12 compounds as TLN inhibitors by virtual screening and in vitro competitive binding assays. However, the specific interactions between TLN and these inhibitors have not been clarified. We here investigate stable structures of the solvated TLN-inhibitor complexes by classical molecular mechanics simulations and elucidate the specific interactions between TLN and these inhibitors at an electronic level by using ab initio fragment molecular orbital (FMO) calculations. The calculated binding energies between TLN and the inhibitors are qualitatively consistent with the experimental results, and the FMO results elucidate important amino acid residues of TLN for inhibitor binding. Based on the calculated results, we propose a novel potent inhibitor having a large binding affinity to TLN.
金属蛋白酶 thermolysin（TLN）的生化功能受各种抑制剂控制。在最近的一项研究中，我们通过虚拟筛选和体外竞争性结合实验鉴定了 12 种化合物作为 TLN 抑制剂。然而，TLN 与这些抑制剂之间的具体相互作用尚未阐明。我们通过经典分子力学模拟研究了溶剂化 TLN-抑制剂复合物的稳定结构，并通过使用从头算片段分子轨道（FMO）计算在电子水平上阐明了 TLN 与这些抑制剂之间的特定相互作用。计算得到的 TLN 与抑制剂之间的结合能与实验结果定性一致，FMO 结果阐明了 TLN 中对抑制剂结合起重要作用的氨基酸残基。基于计算结果，我们提出了一种与 TLN 具有较大结合亲和力的新型强效抑制剂。
