In silico identification of potential SARS COV-2 2'- O -methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations.

Autor:	El Hassab MA; Department of Pharmaceutical Chemistry, School of Pharmacy, Badr University in Cairo (BUC) Cairo Egypt mahmoud65582@pharm.tanta.edu.eg., Ibrahim TM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University Kafrelsheikh Egypt wagdy2000@gmail.com., Shoun AA; Department of Microbiology & Immunology, Faculty of Pharmacy, Sinai University North Sinai Egypt., Al-Rashood ST; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University Riyadh Saudi Arabia., Alkahtani HM; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University Riyadh Saudi Arabia., Alharbi A; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University Riyadh Saudi Arabia., Eskandrani RO; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University Riyadh Saudi Arabia., Eldehna WM; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University Kafrelsheikh Egypt wagdy2000@gmail.com.
Jazyk:	angličtina
Zdroj:	RSC advances [RSC Adv] 2021 Apr 29; Vol. 11 (26), pp. 16026-16033. Date of Electronic Publication: 2021 Apr 29 (Print Publication: 2021).
DOI:	10.1039/d1ra01809d
Abstrakt:	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 ligand-enzyme 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. Competing Interests: The authors declare no conflict of interest. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu