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In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations† † Electronic supplementary information (ESI) available. See DOI: 10.1039/d1ra01809d
RSC advances ; 11(26):16026-16033, 2021.
Article in English | EuropePMC | ID: covidwho-1812711
ABSTRACT
In the present era, there are many efforts trying to face the emerging and successive waves of the COVID-19 pandemic. This has led to considering new and unusual targets for SARS CoV-2. 2′-O-Methyltransferase (nsp16) is a key and attractive target in the SARS CoV-2 life cycle since it is responsible for the viral RNA protection via a cap formation process. In this study, we propose a new potential inhibitor for SARS COV-2 2′-O-methyltransferase (nsp16). A fragment library was screened against the co-crystal structure of the SARS COV-2 2′-O-methyltransferase complexed with Sinefungin (nsp16 – PDB ID 6WKQ), and consequently the best proposed fragments were linked via a de novo approach to build molecule AP-20. Molecule AP-20 displayed a superior docking score to Sinefungin and reproduced the key interactions in the binding site of 2′-O-methyltransferase. Three molecular dynamic simulations of the 2′-O-methyltransferase apo structure and its complexed forms with AP-20 and Sinefungin were performed for 150 nano-seconds to provide insights on the dynamic nature of such setups and to assess the stability of the proposed AP-20/enzyme complex. AP-20/enzyme complex demonstrated better stability for the ligandenzyme complex compared to Sinefungin in a respective setup. Furthermore, MM-PBSA binding free energy calculations showed a better profile for AP-20/enzyme complex compared to Sinefungin/enzyme complex emphasizing the potential inhibitory effect of AP-20 on SARS COV-2 2′-O-methyltransferase. We endorse our designed molecule AP-20 to be further explored via experimental evaluations to confront the spread of the emerging COVID-19. Also, in silico ADME profiling has ascribed to AP-20 an excellent safety and metabolic stability profile. The identification of AP-20 as a potential SARS COV-2 2′-O-methyltransferase inhibitor fragment-based screening approach and MM-PBSA calculations.
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Collection: Databases of international organizations Database: EuropePMC Type of study: Experimental Studies / Prognostic study Language: English Journal: RSC advances Year: 2021 Document Type: Article

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Collection: Databases of international organizations Database: EuropePMC Type of study: Experimental Studies / Prognostic study Language: English Journal: RSC advances Year: 2021 Document Type: Article