| Autor: |
Saramago, Luiz Carlos, Santana, Marcos V., Gomes, Bárbara Figueira, Dantas, Rafael Ferreira, Senger, Mario R., Oliveira Borges, Pedro Henrique, Ferreira, Vivian Neuza dos Santos, dos Santos Rosa, Alice, Tucci, Amanda Resende, Dias Miranda, Milene, Lukacik, Petra, Strain-Damerell, Claire, Owen, C. David, Walsh, Martin Austin, Ferreira, Sabrina Baptista, Silva-Junior, Floriano Paes |
| Zdroj: |
Journal of Chemical Information and Modeling; May 2023, Vol. 63 Issue: 9 p2866-2880, 15p |
| Abstrakt: |
SARS-CoV-2 is the causative agent of COVID-19 and is responsible for the current global pandemic. The viral genome contains 5 major open reading frames of which the largest ORF1ab codes for two polyproteins, pp1ab and pp1a, which are subsequently cleaved into 16 nonstructural proteins (nsp) by two viral cysteine proteases encoded within the polyproteins. The main protease (Mpro, nsp5) cleaves the majority of the nsp’s, making it essential for viral replication and has been successfully targeted for the development of antivirals. The first oral Mpro inhibitor, nirmatrelvir, was approved for treatment of COVID-19 in late December 2021 in combination with ritonavir as Paxlovid. Increasing the arsenal of antivirals and development of protease inhibitors and other antivirals with a varied mode of action remains a priority to reduce the likelihood for resistance emerging. Here, we report results from an artificial intelligence-driven approach followed by in vitrovalidation, allowing the identification of five fragment-like Mpro inhibitors with IC50values ranging from 1.5 to 241 μM. The three most potent molecules (compounds 818, 737, and 183) were tested against SARS-CoV-2 by in vitroreplication in Vero E6 and Calu-3 cells. Compound 818 was active in both cell models with an EC50value comparable to its measured IC50value. On the other hand, compounds 737 and 183 were only active in Calu-3, a preclinical model of respiratory cells, showing selective indexes twice as high as those for compound 818. We also show that our in silicomethodology was successful in identifying both reversible and covalent inhibitors. For instance, compound 818 is a reversible chloromethylamide analogue of 8-methyl-γ-carboline, while compound 737 is an N-pyridyl-isatin that covalently inhibits Mpro. Given the small molecular weights of these fragments, their high binding efficiency in vitroand efficacy in blocking viral replication, these compounds represent good starting points for the development of potent lead molecules targeting the Mpro of SARS-CoV-2. |
| Databáze: |
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