No abstract

Tuberculosis is caused by Mycobacterium tuberculosis and is one of the leading causes of death. Treatment with pyrazinamide depends on the formation of the bioactive species, pyrazinoic acid (POA), catalyzed by the enzyme pyrazinamidase (PZAse). New mutant strains show resistance to PZA, therefore, it is necessary to search for new drugs. Metallodrugs can offer a synergistic effect on the biological activity of the metal and the drug. Recent studies by our group show anti-tuberculosis activity of pyrazinamide coordinated with Zn, however, the mechanism of action is unknown. In this work, an in-silico study was carried out in three stages: Quantum mechanical, molecular docking and molecular dynamics simulations. ZnPZA (Egap = 4.12 eV) presented greater chemical reactivity than PZA (Egap = 4.97 eV). Greater binding energy was found in ZnPZA-PZAse (-6.98 kcal/mol) than in PZA-PZAse (-6.48 kcal/mol). RMSD and RMSF show stability in PZA-PZAse and ZnPZA-PZAse dockings. Hydrogen bonds interaction of ZnPZA with the catalytic amino acids Asp8 and Lys96 occurs for 83 and 40 ns, respectively. It is concluded that ZnPZA could serve as a transporter of PZA to the active site of PZAse, to promote the production of POA and the antituberculous effect; however, further experimental studies are needed.

No abstract

The rapid global spread of SARS-CoV-2, the causative agent of COVID-19, has set off the alarms of healthcare systems all over the world, the situation is exacerbated as no effective treatment is available to date. One therapeutic strategy consists in stopping the replication of the virus by inhibiting SARS-CoV-2 main protease, an important enzyme in the processing of polyproteins from viral RNA. Applying techniques like virtual screening, molecular docking and molecular dynamics simulations, our study evaluated the biomolecular interactions generated between more than 200 thousand natural products structures collected from the Universal Natural Product Database and the main protease active site. Through successive docking filters, we identified 3 molecules with a good affinity profile for the enzyme. These were subjected to molecular dynamics simulations and their binding free energies were calculated. Structures of the best natural products identified could be a starting point for developing novel antiviral candidates targeting SARS-CoV-2 M^pro