Jul 2026· ACS Bio & Med Chem Au· 0 citations· 61 references
TL;DR
The structure-based covalent modifications that generate new nonpeptidic covalent Mpro inhibitors are described that may support the deuterated compound as a new lead for developing anti-SARS-CoV-2 drugs and further reveal the feasibility of using chloroacetyl for structure-based covalent drug design.
Abstract
The main protease (Mpro) is a prime target for anti-SARS-CoV-2 drugs. Herein, we describe the structure-based covalent modifications that generate new nonpeptidic covalent Mpro inhibitors. The compounds exhibit strong inhibition against Mpro at submicromolar levels. The deuterated lead compound exhibits submicromolar antiviral activity against wild-type SARS-CoV-2 and Omicron variants. Biolayer interferometry analysis indicates a strong binding affinity for Mpro. The mass spectrometry results confirm the covalent bonding of the compound with the cysteine residue of Mpro. Taken together, the data may support the deuterated compound as a new lead for developing anti-SARS-CoV-2 drugs and further reveal the feasibility of using chloroacetyl for structure-based covalent drug design.
This study provides binding details for the designed compounds and demonstrates the feasibility of the joint X-ray/neutron structure-assisted drug design approach to generate more potent noncovalent nonpeptidic SARS-CoV-2 MPro inhibitors.
Dipendra Bhandari, Katerina Kovalevskaya, L. Coates et al.· RSC Medicinal Chemistry· 0 citations
COVID-19, caused by SARS-CoV-2, depends on its main protease (Mpro) for viral replication. This study evaluated the potential of polyphenolic compounds from Phoenix dactylifera as Mpro inhibitors using molecular docking, molecular dynamics (MD) simulations, and ADMET profiling. Three ligands - flavoxanthin, violaxanthi...
G. M. Gholam, R. A. P. Irsal, F. R. Mahendra et al.· Letters in Applied NanoBioSc...· 0 citations
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A low molecular weight non-peptide, heterocyclic inhibitor, that inactivates Mpro, an important enzyme for the viral cycle and its inhibition affects replication and infection propagation in SARS-CoV-2.
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Although several SARS-CoV-2 main protease (Mpro) inhibitors have been clinically authorized, the continued evolution of SARS-CoV-2 and the emergence of resistance-associated mutations highlight the need for additional inhibitor scaffolds with balanced potency, chemical stability, and reversible covalent reactivity. Her...
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