Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain.
Discovery of Taroxaz-104: The first potent antidote of SARS-CoV-2 VOC-202012/01 strain.
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DOI：
10.1016/j.molstruc.2021.131106
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发表时间：
2021-12-15
影响因子：
3.8
通讯作者：
Rabie AM
中科院分区：
文献类型：
--
作者：
Rabie AM
多羟基酚和含氮杂环化合物是药物化学中最具活性的两种分子，因为它们中的每一种都以其对人类的各种生物活性而闻名。它们的突出作用之一是抗病毒活性，如果两类的主要功能实体相遇成一个化合物，则抗病毒活性明显显现。最近的COVID-19大流行促使我们针对主要的冠状病毒蛋白/酶靶点计算筛选和评估我们的合成2-（3，4，5-三羟基苯基）-1，3，4-恶二唑小库。令人惊讶的是，很少有配体表现出有趣的低结合能（强抑制亲和力）与一些SARS-CoV-2蛋白，主要是关键酶RNA依赖性RNA聚合酶（nCoV-RdRp）。其中一种化合物是Taroxaz-104（5，5 ′-{5，5 ′-[（1 R，2 R）-1，2-二羟基乙烷-1，2-二基]双（1，3，4-恶二唑-5，2-二基）}二苯-1，2，3-三醇）的结合自由能较低，分别为-10.60和-9.10 kcal/mol（与参比试剂GS-443902相比，其呈现约-9.20和-7.90 kcal/mol）分别与nCoV-RdRp-RNA和单独的nCoV-RdRp。广泛的分子建模检查揭示了Taroxaz-104对nCoV-RdRp的一个可能的活性/变构位点的有效抑制，因为Taroxaz-104分子与该nCoV-RdRp活性位点的推定口袋/空腔的至少7个主要氨基酸相互作用。在获得令人满意的抗COVID-19生物测定结果后，实现了Taroxaz-104分子的有效再利用，因为这些数据表明Taroxaz-104显示出非常有效的抗COVID-19作用（抗SARS-CoV-2 EC 50 = 0.42 μM），对新的SARS-CoV-2菌株具有特定的有希望的疗效。关于Taroxaz-104和其他相关多酚2，5-二取代-1，3，4-恶二唑类似物作为成功的抗SARS-CoV-2药物的进展的其他研究，例如，临床前/临床试验是迫切需要的。
Polyhydroxyphenols and nitrogenous heterocyclics are two of the most powerful active species of molecules in pharmaceutical chemistry, as each of them is renowned for its various bioactivities for humans. One of their outstanding actions is the antiviral activities, which clearly appear if the principal functional entities of both classes meet into one compound. The recent COVID-19 pandemic pushed us to computationally sift and assess our small library of synthetic 2-(3,4,5-trihydroxyphenyl)-1,3,4-oxadiazoles against the main coronaviral protein/enzymatic targets. Surprisingly, few ligands exhibited interesting low binding energies (strong inhibitory affinities) with some SARS-CoV-2 proteins, mainly the pivotal enzyme RNA-dependent RNA polymerase (nCoV-RdRp). One of these compounds was Taroxaz-104 (5,5′-{5,5′-[(1R,2R)-1,2-dihydroxyethane-1,2-diyl]bis(1,3,4-oxadiazole-5,2-diyl)}dibenzene-1,2,3-triol), which presented lower binding free energies of about -10.60 and -9.10 kcal/mol (as compared to the reference agent, GS-443902, which presented about -9.20 and -7.90 kcal/mol) with nCoV-RdRp-RNA and nCoV-RdRp alone, respectively. Extensive molecular modeling examination disclosed the potent Taroxaz-104 inhibition of one of the possible active/allosteric sites of nCoV-RdRp, since Taroxaz-104 molecule interacts with at least seven main amino acids of the presumed pocket/cavity of this nCoV-RdRp active site. The effective repurposing of Taroxaz-104 molecule was attained after the satisfactorily interesting results of the anti-COVID-19 bioassay were secured, since these data demonstrated that Taroxaz-104 showed very efficient anti-COVID-19 actions (anti-SARS-CoV-2 EC50 = 0.42 μM) with specific promising efficacy against the new SARS-CoV-2 strains. Additional research studies for the progress of Taroxaz-104 and other related polyphenolic 2,5-disubstituted-1,3,4-oxadiazole analogs as successful anti-SARS-CoV-2 medications, via, e.g., preclinical/clinical trials, are pressingly required.
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影响因子：
6.1
作者：
Elfiky, Abdo A.
通讯作者：
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