IEEE/ACM Trans Comput Biol Bioinform. 2021 Jul-Aug;18(4):1262-1270. doi: 10.1109/TCBB.2020.3037136. Epub 2021 Aug 6.
SARS-CoV-2 encodes the Mac1 domain within the large nonstructural protein 3 (Nsp3), which has an ADP-ribosylhydrolase activity conserved in other coronaviruses. The enzymatic activity of Mac1 makes it an essential virulence factor for the pathogenicity of coronavirus (CoV). They have a regulatory role in counteracting host-mediated antiviral ADP-ribosylation, which is unique part of host response towards viral infections. Mac1 shows highly conserved residues in the binding pocket for the mono and poly ADP-ribose. Therefore, SARS-CoV-2 Mac1 enzyme is considered as an ideal drug target and inhibitors developed against them can possess a broad antiviral activity against CoV. ADP-ribose-1 phosphate bound closed form of Mac1 domain is considered for screening with large database of ZINC. XP docking and QPLD provides strong potential lead compounds, that perfectly fits inside the binding pocket. Quantum mechanical studies expose that, substrate and leads have similar electron donor ability in the head regions, that allocates tight binding inside the substrate-binding pocket. Molecular dynamics study confirms the substrate and new lead molecules presence of electron donor and acceptor makes the interactions tight inside the binding pocket. Overall binding phenomenon shows both substrate and lead molecules are well-adopt to bind with similar binding mode inside the closed form of Mac1.
SARS-CoV-2 在其大型非结构蛋白 3（Nsp3）中编码 Mac1 结构域，该结构域在其他冠状病毒中具有保守的 ADP-核糖基水解酶活性。Mac1 的酶活性使其成为冠状病毒（CoV）致病性的必需毒力因子。它们在拮抗宿主介导的抗病毒 ADP-核糖基化方面具有调节作用，这是宿主对病毒感染的独特反应的一部分。Mac1 在结合口袋中显示出对单和多 ADP-核糖基的高度保守残基。因此，SARS-CoV-2 Mac1 酶被认为是一个理想的药物靶点，针对它们开发的抑制剂可以对 CoV 具有广泛的抗病毒活性。ADP-核糖-1 磷酸结合的 Mac1 结构域封闭形式被认为可用于 ZINC 大型数据库的筛选。XP 对接和 QPLD 提供了强有力的潜在先导化合物，它们完美地适合于结合口袋内。量子力学研究表明，在头部区域，底物和先导具有相似的电子供体能力，这在底物结合口袋内分配了紧密的结合。分子动力学研究证实，底物和新的先导分子具有电子供体和受体，使得在结合口袋内的相互作用紧密。整体结合现象表明，底物和先导分子都以相似的结合模式很好地适应于封闭形式的 Mac1 结合。
