As a growing number of clinical isolates of Mycobacterium abscessus are resistant to most antibiotics, new treatment options that are effective against these drug-resistant strains are desperately needed. The majority of the linkages in the cell wall peptidoglycan of M. abscessus are synthesized by nonclassical transpeptidases, namely, the l , d -transpeptidases. Emerging evidence suggests that these enzymes represent a new molecular vulnerability in this pathogen. Recent studies have demonstrated that inhibition of these enzymes by the carbapenem class of β-lactams determines their activity against Mycobacterium tuberculosis . Here, we studied the interactions of β-lactams with two l , d -transpeptidases in M. abscessus , namely, Ldt _Mab1 and Ldt _Mab2 , and found that both the carbapenem and cephalosporin, but not penicillin, subclasses of β-lactams inhibit these enzymes. Contrary to the commonly held belief that combination therapy with β-lactams is redundant, doripenem and cefdinir exhibit synergy against both pansusceptible M. abscessus and clinical isolates that are resistant to most antibiotics, which suggests that dual-β-lactam therapy has potential for the treatment of M. abscessus . Finally, we solved the first crystal structure of an M. abscessus l , d -transpeptidase, Ldt _Mab2 , and using substitutions of critical amino acids in the catalytic site and computational simulations, we describe the key molecular interactions between this enzyme and β-lactams, which provide an insight into the molecular basis for the relative efficacy of different β-lactams against M. abscessus .

Tyrosinase is a key enzyme in melanin synthesis and widely distributed in plants and animals tissues. In mammals, this enzyme is related to pigment production, involved in wound healing, primary immune response and it can also contribute to catecholamines synthesis in the brain. Consequently, tyrosinase enzyme represents an attractive and selective target in the field of the medicine, cosmetics and bio-insecticides. In this paper, experimental kinetics and computational analysis were used to study the inhibition of tyrosinase by analogous of Kojic acid. The main interactions occurring between inhibitors-tyrosinase complexes and the influence of divalent cation (Cu²⁺) in enzymatic inhibition were investigated by using molecular docking, molecular dynamic simulations and electrostatic binding free energy by using the Linear Interaction Energy (LIE) method. The results showed that the electrostatic binding free energy are correlated with values of constant inhibition (r² = 0.97).Thus, the model obtained here could contribute to future studies of this important system and, therefore, eventually facilitate development of tyrosinase inhibitors.

Fusarium disease causes considerable losses in the cultivation of Piper nigrum, the black pepper used in the culinary world. Brazil was the largest producer of black pepper, but in recent years has lost this hegemony, with a significant reduction in its production, due to the ravages produced by the Fusarium solani f. sp. piperis, the fungus which causes this disease. Scientific research seeks new alternatives for the control and the existence of other Piper species in the Brazilian Amazon, resistant to disease, are being considered in this context. The main constituents of the oil of Piper divaricatum are methyleugenol (75.0%) and eugenol (10.0%). The oil and these two main constituents were tested individually at concentrations of 0.25 to 2.5 mg/mL against F. solani f. sp. piperis, exhibiting strong antifungal index, from 18.0% to 100.0%. The 3D structure of the β-glucosidase from Fusarium solani f. sp. piperis, obtained by homology modeling, was used for molecular docking and molecular electrostatic potential calculations in order to determine the binding energy of the natural substrates glucose, methyleugenol and eugenol. The results showed that β-glucosidase (Asp45, Arg113, Lys146, Tyr193, Asp225, Trp226 and Leu99) residues play an important role in the interactions that occur between the protein-substrate and the engenol and methyleugenol inhibitors, justifying the antifungal action of these two phenylpropenes against Fusarium solani f. sp. piperis.

The SARS-CoV-2 targets were evaluated for a set of FDA-approved drugs using a combination of drug repositioning and rigorous computational modeling methodologies such as molecular docking and molecular dynamics (MD) simulations followed by binding free energy calculations. Six FDA-approved drugs including, Ouabain, Digitoxin, Digoxin, Proscillaridin, Salinomycin and Niclosamide with promising anti-SARS-CoV-2 activity were screened in silico against four SARS-CoV-2 proteins—papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), SARS-CoV-2 main protease (Mpro), and adaptor-associated kinase 1 (AAK1)—in an attempt to define their promising targets. The applied computational techniques suggest that all the tested drugs exhibited excellent binding patterns with higher scores and stable complexes compared to the native protein cocrystallized inhibitors. Ouabain was suggested to act as a dual inhibitor for both PLpro and Mpro enzymes, while Digitoxin bonded perfectly to RdRp. In addition, Salinomycin targeted PLpro. Particularly, Niclosamide was found to target AAK1 with greater affinity compared to the reference drug. Our study provides comprehensive molecular-level insights for identifying or designing novel anti-COVID-19 drugs.