This study aimed to evaluate the effect of a methoxylated fraction from Vellozia dasypus Seub on myeloperoxidase (MPO)-chlorinating activity and subsequent in silico assays for binding profile prediction. Therefore, the ethyl acetate extract of aerial parts from Vellozia dasypus Seub was fractionated on open-column chromatography containing SiO₂ and eluted with solvent in crescent polarity to yield a fraction with a mixture of flavonols quercetin 3-O-methyl ether (1) and 6-C-methyl quercetin 3-O-methyl ether (2). Their chemical structures were proposed by HPLC coupled to photodiode array (HPLC-DAD) and mass spectrometer using electrospray ionization multistage analysis (HPLC-MS/MS). The fraction enriched with compounds 1 and 2 inhibited more efficiently the in vitro MPO-chlorinating activity (IC₅₀ = 40 µg/mL) than the ethyl acetate extract (IC₅₀ = 64.0 µg/mL). Molecular docking studies revealed that these compounds interact with MPO active pocket similarly to trifluoromethyl-substituted aromatic hydroxamate, a well-known MPO inhibitor, co-crystallized at the MPO binding site (PDB ID: 4C1M). Molecular dynamics trajectories confirmed that these two molecules interact with the MPO binding site with a similar energetic pattern when compared to the crystallographic ligand. Taken together, these data expand the sources of phenolic natural compounds that may be further investigated against inflammation-related diseases. Communicated by Ramaswamy H. Sarma

An unreported prenylated indole derivative hydroxytakakiamide (4) was isolated, together with the previously described ergosterol (1), ergosterol acetate (2), and (3R)-3-(1H-indol-3-ylmethyl)-3, 4-dihydro-1H-1,4-benzodiazepine-2,5-dione (3), from the column fractions of the crude ethyl acetate extract of the culture of a marine sponge-associated fungus, Aspergillus fischeri MMERU 23. The structure of 4 was elucidated by the interpretation of 1D and 2D NMR spectral data and high-resolution mass spectrum. The absolute configuration of the stereogenic carbon in 3 was proposed to be the same as those of the co-occurring congeners on the basis of their biogenetic consideration and was supported by the comparison of its sign of optical rotation with those of its steroisomers. The crude ethyl acetate extract and 2 were evaluated, together with acetylaszonalenin (5) and helvolic acid (6), which were previously isolated from the same extract, for the in vivo antinociceptive activity in the mice model. The crude ethyl acetate extract exhibited antinociceptive activity in the acetic acid-induced writhing and formalin tests, while 2, 5, and 6 displayed the effects in the late phase of the formalin test. On the other hand, neither the crude ethyl acetate extract nor 2, 5, and 6 affected the motor performance of mice in both open-field and rotarod tests. Additionally, docking studies of 2, 5, and 6 were performed with 5-lipoxygenase (5-LOX) and phosphodiesterase (PDE) enzymes, PDE4 and PDE7, which are directly related to pain and inflammatory processes. Molecular docking showed that 6 has low affinity energy to PDE4 and PDE7 targets while retaining high affinity to 5-LOX. On the other hand, while 2 did not display any hydrogen bond interactions in any of its complexes, it achieved overall better energy values than 6 on the three antinociceptive targets. On the other hand, 5 has the best energy profile of all the docked compounds and was able to reproduce the crystallographic interactions of the 5-LOX complex.

The visceral form of Leishmaniasis, also known as kala-azar, caused by Leishmania chagasi is the main etiological agent of this form in Brazil responsible for 30,000 annual deaths. Despite its epidemiological impact, treatment of the disease is limited by resistance, species-dependent efficacy and serious adverse effects. The application of computational tools to prioritize potential bioactive molecules based on 3D structural of biological target is a viable alternative. Among the L. chagasi validated targets, Fe + 2 superoxide dismutase B2 (LcFeSODB2) is the first parasite enzyme against oxidative stress and it is involved in essential metabolic processes for its survival. Due to substrate binding-site volume (superoxide ion) and consequent difficulty in its active site modulation for small molecules, the search for allosteric sites at LcFeSODB2 3D structure is a promising strategy. As there are no 3D structures of LcFeSODB2, comparative modeling was applied to build 3D models by SWISS-MODEL and MODELLER version 9.19. Next, the best 3D model was used in molecular dynamics (MD) routines with multiple probes on GROMACS version 5.1.2. In addition, potential allosteric sites predicted by FTMap and Metapocket web servers were used with probe occupancy maps from MD to select an allosteric binding site and propose a pharmacophore model. Next, it was used as a template in virtual screening by UNITY^® module available on SYBYL-X version 2.1.1 at Sigma-Aldrich CPR™ subset of ZINC12 database. The pharmacophore-based virtual screening resulted in the selection of two potential allosteric LcFeSOD compounds with partial pharmacophoric requirements, drug-like properties and commercial availability for enzymatic assays. Communicated by Ramaswamy H. Sarma

Marine-derived fungi are a promising source of bioactive molecules, especially species from extreme habitats. Although several secondary metabolites such as meroterpenoids and alkaloids have been isolated from cultures of Aspergillus fischeri, obtained from terrestrial habitats, there is no report on compounds isolated from marine-derived strains. Many metabolites isolated from marine-derived fungi exhibited a myriad of biological activities. Marine natural products have shown to be an important source of bioactive compounds and can assist in the discovery of molecules with affinity against validated targets from exclusive strains of parasites of medical importance such as pteridine reductase 1 (PTR1), from Leishmania major, which is essential for cell growth. Leishmaniasis is responsible for approximately 65,000 annual deaths. Despite the mortality data, drugs available for the treatment of patients are insufficient and have moderate therapeutic efficacy in addition to serious adverse effects, which make the development of new drugs urgent. The previously described aszonalenin (ASL), aszonapyrone A (ASP), acetylaszonalenin (ACZ), and helvolic acid (HAC) were isolated from the ethyl acetate extract of the culture of a marine sponge-associated A. fischeri MMERU 23 and their affinities against PTR1 were determined by ThermoFluor®. Among the tested compounds, only ACZ showed dose-dependent affinity against PTR1. Moreover, complementary molecular dynamics studies (t = 100 000 ps) have showed that this molecule performs hydrogen bonds with key residues at the active site for more than 60% of the productive trajectory time. The results indicate that ACZ could be a promising PTR1 inhibitor and a potential candidate for development of antileishmanial drug. Communicated by Ramaswamy H. Sarma