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Multistaged In Silico Discovery of the Best SARS-CoV-2 Main Protease Inhibitors amongst 3009 Clinical and FDA-Approved Compounds.
- Source :
- Journal of Chemistry; 3/6/2024, Vol. 2024, p1-19, 19p
- Publication Year :
- 2024
-
Abstract
- As a follow-up to our teamwork's former work against SARS-CoV-2, eight compounds (ramelteon (68), prilocaine (224), nefiracetam (339), cyclandelate (911), mepivacaine (2325), ropivacaine (2351), tasimelteon (2384), and levobupivacaine (2840)) were revealed as the best potentially active SARS-CoV-2 inhibitors targeting the main protease (PDB ID: 5R84), M<superscript>pro</superscript>. The compounds were named in the midst of 3009 FDA and clinically approved compounds employing a multistaged in silico method. A molecular fingerprints study with GWS, the cocrystallized ligand of the M<superscript>pro</superscript>, indicated the resemblance of 150 candidates. Consequently, a structure similarity experiment disclosed the best twenty-nine analogous. Then, molecular docking studies were done against the M<superscript>pro</superscript> active site and showed the binding of the best compounds. Next, a 3D-pharmacophore study confirmed the obtained results for the eight compounds by exhibiting relative fit values of more than 90% (except for 68, 74%, and 2384, 83%). Levobupivacaine (2840) showed the most accurate docking and pharmacophore scores and was picked for further MD simulations experiments (RMSD, RMSF, R<subscript>g</subscript>, SASA, and H-H bonding) over 100 ns. The MD simulations results revealed the accurate binding as well as the optimum dynamics of the M<superscript>pro</superscript>-levobupivacaine complex. Finally, MM-PBSA studies were conducted and indicated the favorable bonding of the M<superscript>pro</superscript>-levobupivacaine complex with a free energy value of −235 kJ/mol. The fulfilled outcomes hold out hope of beating COVID-19 through more in vitro and in vivo research for the named compounds. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 20909063
- Volume :
- 2024
- Database :
- Complementary Index
- Journal :
- Journal of Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 176041423
- Full Text :
- https://doi.org/10.1155/2024/2176512