Structural and Mechanistic Insights into the Main Protease (Mpro) Dimer Interface Destabilization Inhibitor: Unveiling New Therapeutic Avenues against SARS-CoV-2Click to copy article linkArticle link copied!
- Ankur SinghAnkur SinghDepartment of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, Uttarakhand 247667, IndiaMore by Ankur Singh
- Kuldeep JangidKuldeep JangidDepartment of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, Uttarakhand 247667, IndiaMore by Kuldeep Jangid
- Sanketkumar NehulSanketkumar NehulDepartment of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, Uttarakhand 247667, IndiaMore by Sanketkumar Nehul
- Preeti DhakaPreeti DhakaDepartment of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, Uttarakhand 247667, IndiaMore by Preeti Dhaka
- Ruchi RaniRuchi RaniDepartment of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, Uttarakhand 247667, IndiaMore by Ruchi Rani
- Akshay PareekAkshay PareekDepartment of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, Uttarakhand 247667, IndiaMore by Akshay Pareek
- Gaurav Kumar Sharma*Gaurav Kumar Sharma*Email: [email protected]Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh 243122, IndiaMore by Gaurav Kumar Sharma
- Pravindra Kumar*Pravindra Kumar*Email: [email protected]Department of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, Uttarakhand 247667, IndiaMore by Pravindra Kumar
- Shailly Tomar*Shailly Tomar*Email: [email protected]Department of Biosciences and Bioengineering, Indian Institute of Technology, Roorkee, Uttarakhand 247667, IndiaMore by Shailly Tomar
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 IC50 values in the range from 0.64 to 11.98 μM. Additionally, in vitro cell-based antiviral assays showed high efficacy with EC50 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.
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