3255 TAMU, College Station, TX, 77843, USA.
Dalton Trans. 2021 Sep 14;50(35):12226-12233. doi: 10.1039/d1dt02499j.
Numerous organic molecules are known to inhibit the main protease of SARS-CoV-2, (SC2M), a key component in viral replication of the 2019 novel coronavirus. We explore the hypothesis that zinc ions, , bind to the SC2M enzyme in combination with lipophilic tropolone and thiotropolone ligands, , block substrate docking, and inhibit function. This study combines synthetic inorganic chemistry, protease activity assays, and computational modeling. While the ligands themselves have half maximal inhibition concentrations, IC, for SC2M in the 8-34 μM range, the IC values are 100 nM for Zn(NO) which are further enhanced in Zn- combinations (59-97 nM). Isolation of the Zn() binary complexes and characterization of their ability to undergo ligand displacement is the basis for computational modeling of the chemical features of the enzyme inhibition. Blind docking onto the SC2M enzyme surface using a modified Autodock4 protocol found preferential binding into the active site pocket. Such Zn- combinations orient so as to permit dative bonding of Zn() to basic active site residues.
许多有机分子已被证实可抑制 SARS-CoV-2 的主要蛋白酶（SC2M），这是 2019 年新型冠状病毒复制的关键组成部分。我们提出假设，锌离子与亲脂性的三羟甲基噁唑啉和硫代三羟甲基噁唑啉配体结合，形成锌配合物，从而抑制 SC2M 酶的功能。本研究结合了合成无机化学、蛋白酶活性测定和计算建模。虽然配体本身对 SC2M 的半数最大抑制浓度（IC）在 8-34 μM 范围内，但 Zn(NO)的 IC 值为 100 nM，而 Zn-配合物进一步增强（59-97 nM）。Zn()二元配合物的分离及其对配体置换能力的表征是对酶抑制化学特征进行计算建模的基础。使用改良的 Autodock4 协议对 SC2M 酶表面进行盲态对接，发现优先结合到活性位点口袋。这种 Zn-配合物的定向排列允许 Zn()与活性位点的碱性残基形成配位键。
