RESUMEN
This study aimed to identify potential inhibitors and investigate the mechanism of action on SARS-CoV-2 ACE2 receptors using a molecular modeling study and theoretical determination of biological activity. Hydroxychloroquine was used as a pivot structure and antimalarial analogues of 1,2,4,5 tetraoxanes were used for the construction and evaluation of pharmacophoric models. The pharmacophore-based virtual screening was performed on the Molport® database (~7.9 million compounds) and obtained 313 structures. Additionally, a pharmacokinetic study was developed, obtaining 174 structures with 99% confidence for human intestinal absorption and penetration into the blood-brain barrier (BBB); posteriorly, a study of toxicological properties was realized. Toxicological predictions showed that the selected molecules do not present a risk of hepatotoxicity, carcinogenicity, mutagenicity, and skin irritation. Only 54 structures were selected for molecular docking studies, and five structures showed binding affinity (ΔG) values satisfactory for ACE2 receptors (PDB 6M0J), in which the molecule MolPort-007-913-111 had the best ΔG value of -8.540 Kcal/mol, followed by MolPort-002-693-933 with ΔG = -8.440 Kcal/mol. Theoretical determination of biological activity was realized for 54 structures, and five molecules showed potential protease inhibitors. Additionally, we investigated the Mpro receptor (6M0K) for the five structures via molecular docking, and we confirmed the possible interaction with the target. In parallel, we selected the TopsHits 9 with antiviral potential that evaluated synthetic accessibility for future synthesis studies and in vivo and in vitro tests.
Asunto(s)
Hidroxicloroquina/farmacología , SARS-CoV-2/efectos de los fármacos , Tetraoxanos/farmacología , Antivirales/farmacología , Sitios de Unión , Biología Computacional/métodos , Evaluación Preclínica de Medicamentos/métodos , Humanos , Hidroxicloroquina/análogos & derivados , Simulación del Acoplamiento Molecular/métodos , Simulación de Dinámica Molecular , Inhibidores de Proteasas/farmacología , Unión Proteica/efectos de los fármacos , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/metabolismo , Tratamiento Farmacológico de COVID-19RESUMEN
Endophytic fungi are microorganisms capable of colonizing the interior of plant tissues without causing damage to them. The study of the secondary metabolites produced by their vast biodiversity fungal is relevant for the discovery of new products for biotechnological and agrochemical applications. In addition, extract of the endophytic fungus Aspergillus sp., isolated from the almonds of Bertholletia excelsa Humn & Bonlp collected in the Brazilian Amazon, oviposition deterrent, and larvicidal activity of against Aedes aegypti. In the oviposition deterrence test was observed that females able to lay eggs preferred the control oviposition sites (46.6%). Furthermore, the extract showed larvicidal activity with LC50 26.86 µg/mL at 24 h and 18.75 µg/mL at 48 h. Molecular docking studies showed the compound Aspergillol B a potent larvicide by to inhibit the acetylcholinesterase enzyme (- 7.74 kcal/mol). These results indicate that compounds from secondary metabolites of Aspergillus sp., isolated from almonds of B. excelsa, are useful biological potential against vectors A. aegypti.