组织蛋白酶 L 抑制剂在木瓜蛋白酶结合位点的分子对接。,Journal of Chemical Information and Modeling

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组织蛋白酶 L 抑制剂在木瓜蛋白酶结合位点的分子对接。
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2008 Jul , DOI: 10.1021/ci800085c
Mary Pat Beavers ₁ , Michael C Myers , Parag P Shah , Jeremy E Purvis , Scott L Diamond , Barry S Cooperman , Donna M Huryn , Amos B Smith

Affiliation

木瓜蛋白酶/CLIK-148 坐标系被用作模型来研究组织蛋白酶 L (1) 的非肽硫代氨基甲酸盐抑制剂的相互作用。这种小分子抑制剂是一种含有二酰基肼官能团和一个立体中心的硫羟酸酯，作为 S-对映异构体最为活跃，IC 50 为 56 nM；R-对映异构体 (2) 仅显示微弱的活性 (33 microM)。相应地，Extra Precision Glide 的分子对接研究揭示了保留结构水时两种硫代氨基甲酸酯对映体的评分与生物活性之间的相关性。1 和木瓜蛋白酶之间的分子相互作用与观察到的 CLIK-148（3a 和 3b）与木瓜蛋白酶的相互作用非常相似，特别是关于配体与催化结合位点中保守残基的氢键和亲脂相互作用。随后在结合位点对接虚拟化合物导致鉴定出更有效的抑制剂 (5)，IC 50 为 7.0 nM。这些对接研究表明，当虚拟化合物设计包括通过配体的疏水性和芳香性官能团占据 S2、S3 和 S1' 亚位点，以及之间至少三个氢键接触时，可以实现有利的能量得分和相应有利的生物活性。配体和蛋白质的保守结合位点残基。

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Molecular docking of cathepsin L inhibitors in the binding site of papain.

The papain/CLIK-148 coordinate system was employed as a model to study the interactions of a nonpeptide thiocarbazate inhibitor of cathepsin L ( 1). This small molecule inhibitor, a thiol ester containing a diacyl hydrazine functionality and one stereogenic center, was most active as the S-enantiomer, with an IC 50 of 56 nM; the R-enantiomer ( 2) displayed only weak activity (33 microM). Correspondingly, molecular docking studies with Extra Precision Glide revealed a correlation between score and biological activity for the two thiocarbazate enantiomers when a structural water was preserved. The molecular interactions between 1 and papain were very similar to the interactions observed for CLIK-148 ( 3a and 3b) with papain, especially with regard to the hydrogen-bonding and lipophilic interactions of the ligands with conserved residues in the catalytic binding site. Subsequent docking of virtual compounds in the binding site led to the identification of a more potent inhibitor ( 5), with an IC 50 of 7.0 nM. These docking studies revealed that favorable energy scores and correspondingly favorable biological activities could be realized when the virtual compound design included occupation of the S2, S3, and S1' subsites by hydrophobic and aromatic functionalities of the ligand, and at least three hydrogen bonding contacts between the ligand and the conserved binding site residues of the protein.

更新日期：2017-01-31

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