Department of Chemistry, Texas A&M University, College Station, Texas 77842-3012, USA.
Chem Commun (Camb). 2021 Aug 28;57(67):8352-8355. doi: 10.1039/d1cc03103a. Epub 2021 Aug 2.
By repurposing DNICs designed for other medicinal purposes, the possibility of protease inhibition was investigated in silico using AutoDock 4.2.6 (AD4) and in vitro via a FRET protease assay. AD4 was validated as a predictive computational tool for coordinatively unsaturated DNIC binding using the only known crystal structure of a protein-bound DNIC, PDB- (calculation RMSD = 1.77). From the in silico data the dimeric DNICs TGTA-RRE, [(μ-S-TGTA)Fe(NO)] (TGTA = 1-thio-β-d-glucose tetraacetate) and TG-RRE, [(μ-S-TG)Fe(NO)] (TG = 1-thio-β-d-glucose) were identified as promising leads for inhibition via coordinative inhibition at Cys-145 of the SARS-CoV-2 Main Protease (SC2M). In vitro studies indicate inhibition of protease activity upon DNIC treatment, with an IC of 38 ± 2 μM for TGTA-RRE and 33 ± 2 μM for TG-RRE. This study presents a simple computational method for predicting DNIC-protein interactions; the in vitro study is consistent with in silico leads.
通过重新利用为其他药用目的设计的 DNIC，可以使用 AutoDock 4.2.6（AD4）进行计算机模拟，并通过 FRET 蛋白酶测定进行体外研究来探索蛋白酶抑制的可能性。AD4 通过使用唯一已知的与蛋白质结合的 DNIC 的晶体结构（PDB-）进行了验证，作为协调不饱和 DNIC 结合的预测计算工具（计算 RMSD = 1.77）。从计算机模拟数据中，二聚体 DNICs TGTA-RRE、[(μ-S-TGTA)Fe(NO)]（TGTA = 1-硫-β-d-葡萄糖四乙酸酯）和 TG-RRE、[(μ-S-TG)Fe(NO)]（TG = 1-硫-β-d-葡萄糖）被鉴定为通过与 SARS-CoV-2 主要蛋白酶（SC2M）的 Cys-145 协调抑制抑制的有前途的先导物。体外研究表明，DNIC 处理后蛋白酶活性受到抑制，TGTA-RRE 的 IC 为 38 ± 2 μM，TG-RRE 的 IC 为 33 ± 2 μM。本研究提出了一种预测 DNIC-蛋白质相互作用的简单计算方法；体外研究与计算机模拟结果一致。
