Evaluation of acridinedione analogs as potential SARS-CoV-2 main protease inhibitors and their comparison with repurposed anti-viral drugs.
Evaluation of acridinedione analogs as potential SARS-CoV-2 main protease inhibitors and their comparison with repurposed anti-viral drugs.
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DOI：
10.1016/j.compbiomed.2020.104117
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发表时间：
2021-01
影响因子：
7.7
通讯作者：
Purohit R
中科院分区：
文献类型：
--
作者：
Bhardwaj VK;Singh R;Das P;Purohit R
SARS-CoV-2的主要蛋白酶（Mpro）参与病毒基因组复制和转录所需的重要多肽的加工，并且是抑制SARS-CoV-2在感染个体中的进展的最佳表征的靶标之一。我们筛选了一组新的吖啶二酮类分子，通过靶向Mpro有效地结合并抑制SARS-CoV-2的活性。将FDA批准的再利用的抗病毒药物作为本研究的标准分子。进行长时程（1.1 μs）MD模拟以分析与所选分子结合的Mpro结合口袋的构象空间。分子DSPD-2和DSPD-6显示出更有利的MM-PBSA相互作用能，并且比最顶级的抗病毒药物（沙奎那韦）更深地位于Mpro的结合口袋内。此外，DSPD-5也表现出与沙奎那韦相当的结合能。单残基贡献能分析和SASA研究表明，分子通过靶向Mpro结合口袋的S1亚位点而显示出有效的结合。DSPD-2、DSPD-6和DSPD-5可作为潜在的SARS-CoV-2抑制剂。此外，我们认为靶向分子有效地结合到S1亚位点可能会增加分子与SARS-CoV-2 Mpro的结合。一个强大的计算策略应用于识别COVID-19的潜在线索。将FDA批准的重新使用的抗病毒药物与一组吖啶二酮类似物进行比较，以对抗SARS-CoV-2的Mpro。吖啶二酮类似物具有可接受的ADMET值和低毒性特征。内部合成的吖啶二酮类似物与SARS-CoV-2的Mpro表现出良好的相互作用。
The main protease (Mpro) of SARS-CoV-2 is involved in the processing of vital polypeptides required for viral genome replication and transcription and is one of the best-characterized targets to inhibit the progression of SARS-CoV-2 in infected individuals. We screened a set of novel classes of acridinediones molecules to efficiently bind and inhibit the activity of the SARS-CoV-2 by targeting the Mpro. The repurposed FDA-approved antivirals were taken as standard molecules for this study. Long term (1.1 μs) MD simulations were performed to analyze the conformational space of the binding pocket of Mpro bound to the selected molecules. The molecules DSPD-2 and DSPD-6 showed more favorable MM-PBSA interaction energies and were seated more deeply inside the binding pocket of Mpro than the topmost antiviral drug (Saquinavir). Moreover, DSPD-5 also exhibited comparable binding energy to Saquinavir. The analysis of per residue contribution energy and SASA studies indicated that the molecules showed efficient binding by targeting the S1 subsite of the Mpro binding pocket. The DSPD-2, DSPD-6, and DSPD-5 could be developed as potential inhibitors of SARS-CoV-2. Moreover, we suggest that targeting molecules to bind effectively to the S1 subsite could potentially increase the binding of molecules to the SARS-CoV-2 Mpro. A robust computational strategy applied to identify the potential lead for COVID-19. Repurposed FDA approved antiviral drugs were compared with a set of acridinedione analogs against Mpro of SARS-CoV-2. The acridinedione analogs have acceptable ADMET values and low toxicity profile. In-house synthesized acridinedione analogs showed good amount of interaction with Mpro of SARS-CoV-2.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
DOI：
10.1073/pnas.1812963116
发表时间：
2019-02-12
影响因子：
11.1
作者：
Hillig, Roman C.;Sautier, Brice;Bader, Benjamin
通讯作者：
Bader, Benjamin
影响因子：
3.8
作者：
Khodadadi, Ehsaneh;Maroufi, Parham;Kafil, Hossein Samadi
通讯作者：
Kafil, Hossein Samadi
影响因子：
5.6
作者：
LEE, B;RICHARDS, FM
通讯作者：
RICHARDS, FM
影响因子：
3.7
作者：
HEROLD, J;RAABE, T;SIDDELL, SG
通讯作者：
SIDDELL, SG