Rational Approach toward COVID-19's Main Protease Inhibitors: A Hierarchical Biochemoinformatics Analysis.

This study investigated the potential of selected compounds as inhibitors of SARS-CoV-2 Mpro through pharmacokinetic and toxicological analyses, molecular docking, and molecular dynamics simulations. In silico molecular docking simulations revealed promising ligands with favorable binding affinities for Mpro, ranging from -6.2 to -9.5 kcal/mol. Moreover, molecular dynamics simulations demonstrated the stability of protein-ligand complexes over 200 ns, maintaining protein secondary structures. MM-PBSA analysis revealed favorable interactions between ligands and Mpro, with negative binding energy values. Hydrogen bond formation capacity during molecular dynamics was confirmed, indicating consistent interactions with Mpro catalytic residues. Based on these findings, selected ligands show promise for future studies in developing COVID-19 treatments.

Identification of Potential Antiviral Inhibitors from Hydroxychloroquine and 1,2,4,5-Tetraoxanes Analogues and Investigation of the Mechanism of Action in SARS-CoV-2.

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.

Identification of novel potential cyclooxygenase-2 inhibitors using ligand- and structure-based virtual screening approaches.

Cyclooxygenase 2 (COX-2) is a well-established target for the design of anti-inflammatory intermediates. Celecoxib was selected as a template molecule to perform ligand-based virtual screening, i.e. to search for structures with similarity in shape and electrostatic potential, with a gradual increase in accuracy through the combined fitting of several steps using eight commercial databases. The molecules ZINC408709 and ZINC2090319 reproduced values within the limits established in an initial study of absorption and distribution in the body. No alert was fired for possible toxic groups when these molecules were subjected to toxicity prediction. Molecular docking results with these compounds showed a higher binding affinity in comparison to rofecoxib for the COX-2 target. Additionally, ZINC408709 and ZINC2090319 were predicted to be potentially biologically active. In in silico prediction of endocrine disruption potential, it was established that the molecule ZINC2090319 binds strongly to the target related to cardiovascular risk in a desirable way as a non-steroidal antagonist and ZINC408709 binds strongly to the target that is associated with the treatment of inflammatory pathologies and similar to celecoxib. Metabolites generated from these compounds are less likely to have side effects. Simulations were used to evaluate the interaction of compounds with COX-1 and COX-2 during 200 ns. Despite the differences, ZINC408709 molecule showed better stability for COX-2 during molecular dynamics simulation. In the calculations of free energy MM/PBSA, the molecule ZINC408709 ΔGbind value has a higher affinity to celecoxib and rofecoxib COX-2. This demonstrates that the selected substances can be considered as promising COX-2 inhibitors. Communicated by Ramaswamy H. Sarma.

Does total tannin content explain the use value of spontaneous medicinal plants from the Brazilian semi-arid region?

Due to the current predatory exploitation and consequent extinction of native medicinal plants around the world, strategies have been proposed aiming at the sustainable use of these resources. Accordingly, this study aims at verifying the differences in tannin compounds content in the bark of eleven species with high use value (UV) and also relating the amounts of tannins with their therapeutic indications. To quantify the total phenolic content in the samples the Folin-Ciocalteu reagent was used, and for total tannins chemical casein precipitation was applied. The amount of tannins ranged intra-specifically and the greater variation was found for Anadenanthera colubrina (angico) that displayed between 157.57 and 107.39 mg/g. The lowest variation occurred in Lafoensia replicata (mangabeira) with values ranging between 76.55 and 68.96 mg/g. There were significant differences between several of the eleven species and according to the simple regression analysis, the quantities of tannins found failed to justify their UV. Thus, it was not possible to establish whether the amount of total tannins influenced to a greater or lesser degree in the accumulation of knowledge. Moreover, this is the first study to investigate the relationship between the amount of total tannins and local botanical knowledge expressed by the UV.

Antioxidant, icthyotoxicity and brine shrimp lethality tests of Magonia glabrata.

The ethanolic extract of the fruit bark from Magonia glabrata yielded shikimic acid, scopoletin, sitosterol glycoside and 2-O-methyl-l-inositol. Antioxidant, icthyotoxicity and brine shrimp lethality activities were observed in this extract. The major constituent, 2-O-methyl-l-inositol, was found to be inactive in two assays but showed moderate activity as a radical scavenger.