9J19

The crystal structure of COVID-19 main protease in complex with an inhibitor minocycline

Summary for 9J19

• Entry DOI: 10.2210/pdb9j19/pdb
• Descriptor: 3C-like proteinase nsp5, (4S,4AS,5AR,12AS)-4,7-BIS(DIMETHYLAMINO)-3,10,12,12A-TETRAHYDROXY-1,11-DIOXO-1,4,4A,5,5A,6,11,12A-OCTAHYDROTETRACENE-2- CARBOXAMIDE (2 entities in total)
• Functional Keywords: sars-cov-2, mpro, protease, antiviral, antiviral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 66080.36

Authors

Singh, A.,Jangid, K.,Dhaka, P.,Tomar, S.,Kumar, P. (deposition date: 2024-08-04, release date: 2025-02-12, Last modification date: 2025-04-09)

Primary citation

Singh, A.,Jangid, K.,Nehul, S.,Dhaka, P.,Rani, R.,Pareek, A.,Sharma, G.K.,Kumar, P.,Tomar, S.
Structural and Mechanistic Insights into the Main Protease (Mpro) Dimer Interface Destabilization Inhibitor: Unveiling New Therapeutic Avenues against SARS-CoV-2.
Biochemistry, 64:1589-1605, 2025

PubMed Abstract: SARS-CoV-2 variant recurrence has emphasized the imperative prerequisite for effective antivirals. The main protease (Mpro) of SARS-CoV-2 is crucial for viral replication, making it one of the prime and promising antiviral targets. Mpro features several druggable sites, including active sites and allosteric sites near the dimerization interface, that regulate its catalytic activity. This study identified six highly efficacious antiviral SARS-CoV-2 compounds (WIN-62577, KT185, bexarotene, ledipasvir, diacerein, and simepervir) using structure-based virtual screening of compound libraries against Mpro. Using SPR and ITC, the binding of selected inhibitory compounds to the target Mpro was validated. The FRET-based protease assay demonstrated that the identified molecules effectively inhibit Mpro with IC values in the range from 0.64 to 11.98 μM. Additionally, cell-based antiviral assays showed high efficacy with EC values in the range of 1.51 to 18.92 μM. The crystal structure of the Mpro-minocycline complex detailed the possible inhibition mechanism of minocycline, an FDA-approved antibiotic. Minocycline binds to an allosteric site, revealing residues critical for the loss of protease activity due to destabilization of molecular interactions at the dimeric interface, which are crucial for the proteolytic activity of Mpro. The study suggests that the binding of minocycline to the allosteric site may play a role in Mpro dimer destabilization and direct the rational design of minocycline derivatives as antiviral drugs.

PubMed: 39882595
DOI: 10.1021/acs.biochem.4c00535

Experimental method

X-RAY DIFFRACTION (2.7 Å)