Journal
RSC ADVANCES
Volume 10, Issue 66, Pages 40244-40263Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d0ra08304f
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Funding
- Slovak Research and Development Agency [APVV-17-0239, PP-COVID-20-0010]
- Granting Agency of Slovak Ministry of Education
- Slovak Academy of Sciences [VEGA 1/0228/17]
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Despite the intense development of vaccines and antiviral therapeutics, no specific treatment of coronavirus disease 2019 (COVID-19), caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently available. Recently, X-ray crystallographic structures of a validated pharmacological target of SARS-CoV-2, the main protease (M-pro also called 3CL(pro)) in complex with peptide-like irreversible inhibitors have been published. We have carried out computer-aided structure-based design and optimization of peptidomimetic irreversible alpha-ketoamide M-pro inhibitors and their analogues using MM, MD and QM/MM methodology, with the goal to propose lead compounds with improved binding affinity to SARS-CoV-2 M-pro, enhanced specificity for pathogenic coronaviruses, decreased peptidic character, and favourable drug-like properties. The best inhibitor candidates designed in this work show largely improved interaction energies towards the M-pro and enhanced specificity due to 6 additional hydrogen bonds to the active site residues. The presented results on new SARS-CoV-2 M-pro inhibitors are expected to stimulate further research towards the development of specific anti-COVID-19 drugs.
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