Fabian López-Vallejo

Introduction: Isotretinoin (ITN), a vitamin A derivative commonly used for acne treatment, is limited by safety concerns related to its adverse effects. Protein-based delivery systems represent a promising strategy to improve its therapeutic profile. Collagen (COL), the most abundant mammalian protein, is an attractive biomaterial for drug delivery applications. Aim: This study investigated, using an in silico approach, the interaction between ITN and different human COL types (I, II and III) to evaluate their potential as drug-protein complexes for ITN delivery. Methods: Molecular docking between ITN and COL was performed at two pH values (4.0 and 7.0). Subsequently, 200 ns molecular dynamics (MD) simulations were carried out at each pH for every complex, and binding free energies were estimated using the MM-GBSA method. Results: Molecular docking showed that ITN exhibited the highest affinity for COL I at pH 4.0, followed by COL III, whereas the weakest interaction was observed with COL II. MD simulations suggested that the protonation state of ITN influences complex formation, supporting greater stability at pH 4.0, when ITN is in its non-ionized form. The trajectories also showed multiple potential binding sites within COL, suggesting the possibility of stoichiometries other than 1:1. MM-GBSA calculations revealed the energetic contributions stabilizing the ITN-COL complexes, with the strongest interaction for COL I at pH 4.0. Conclusions: These results suggest that COL I at pH 4.0 is a promising carrier candidate for ITN delivery, with potential applications in the development of safer anti-acne therapeutic strategies.

Lipid metabolism is a vital biological process essential for human health, encompassing key pathways necessary for the survival and homeostasis of all organisms. Liver X Receptors (LXRs) are extensively acknowledged as pivotal regulators of lipid homeostasis and inflammatory responses. Pharmacological activation of Liver X Receptor (LXR) has been shown to increase expression of ApoE and ABCA1 proteins, reducing neurodegeneration in murine models of Alzheimer’s disease. Because previous reports determined that Nectandra reticulata (Lauraceae) extract has agonistic LXRs activity, the objective of this study was to determine the metabolites present in this extract and to evaluate their in silico and in vitro agonistic activity. The chromatographic analysis revealed the presence of three glycosylated flavonols. The in silico study showed that isolated flavonoids generate a hydrogen bond with T302 and T316 (LXRα and LXRβ, respectively). The in vitro study showed that the flavonoids increased the expression of mRNA of both APOE and ABCA1 target genes of LXRs, as observed by qRT-PCR. The bioactive flavonoids isolated in this study possess a documented antioxidant effect; when combined with their LXR agonist activity, they become promising bioactive candidates for use in nutraceutical formulations aimed at promoting brain health and anti-inflammatory effects.

Lipid metabolism is a vital biological process essential for human health, encompassing key pathways necessary for the survival and homeostasis of all organisms. Liver X Recep-tors (LXRs) are extensively acknowledged as pivotal regulators of lipid homeostasis and inflammatory responses. Pharmacological activation of liver X receptor (LXR) has been shown to increase expression of ApoE and ABCA1 reducing neurodegeneration in murine models of Alzheimer´s disease. Because previous reports determined that Nectandra reticu-lata (Lauraceae) extract has agonistic LXRs activity, the objective of this study was to de-termine the metabolites present in this extract and to evaluate their in silico and in vitro agonistic activity. Identification was done by reversed phase (RP) ultra-high performance liquid chromatography (UHPLC) with a diode array detector (DAD) and high resolution mass spectrometry with electrospray ionization (ESI-HR-MS). In silico study was performed by Auto Dock Vina. The in vitro agonist activity was evaluated using real-time re-verse transcription-polymerase chain reaction (qRT-PCR) to determine the RNA expression of ApoE and ABCA1. The chromatographic analysis revealed the presence of three glycosylated flavonols: The in silico study showed that isolated flavonoids generate a hydrogen bond with T302 and T316 (LXRα and LXRβ respectively). The in vitro study showed that the flavonoids increased the expression of mRNA of both APOE and ABCA1 target genes of LXRs, as observed by qRT-PCR. The bioactive flavonoids isolated in this study possess documented antioxidant effect, when combined with their LXR agonist activity, they become promising bioactive candidates for use in nutraceutical formulations aimed at promoting brain health and anti-inflammatory effects.

Digestive enzymes are currently considered important therapeutic targets for the treatment of obesity and some associated metabolic diseases, such as type 2 diabetes. Piper cumanense is a species characterized by the presence of bioactive constituents, particularly prenylated benzoic acid derivatives. In this study, the inhibitory potential of chemical constituents from P. cumanense and some synthesized compounds was determined on digestive enzymes (pancreatic lipase (PL) and α-glucosidase (AG)). The methodology included isolating and identifying secondary metabolites from P. cumanense, synthesizing some analogs, and a molecular docking study. The chemical study allowed the isolation of four prenylated benzoic acid derivatives (1–4). Four analogs (5–8) were synthesized. Seven compounds were found to significantly inhibit the catalytic activity of PL with IC₅₀ values between 28.32 and 55.8 µM. On the other hand, only two compounds (6 and 7) were active as inhibitors of AG with IC₅₀ values lower than 155 µM, standing out as the potential multitarget of these chromane compounds. Enzyme kinetics and molecular docking studies showed that the bioactive compounds mainly interact with amino acids other than those of the catalytic site in both PL and AG. This work constitutes the first report on the antidiabetic and antiobesity potential of substances derived from P. cumanense.

Digestive enzymes such α-amylase (AA), α-glucosidase (AG) and pancreatic lipase (PL), play an important role in the metabolism of carbohydrates and lipids, being attractive therapeutic targets for the treatment of type 2 diabetes and obesity. Garcinia mangostana is an interesting species because there have been identified xanthones with the potential to inhibit these enzymes. In this study, the multitarget inhibitory potential of xanthones from G. mangostana against AA, AG and PL was assessed. The methodology included the isolation and identification of bioactive xanthones, the synthesis of some derivatives and a molecular docking study. The chemical study allowed the isolation of five xanthones (1–5). Six derivatives (6–11) were synthesized from the major compound, highlighting the proposal of a new solvent-free methodology with microwave irradiation for obtaining aromatic compounds with tetrahydropyran cycle. Compounds with multitarget activity correspond to 2, 4, 5, 6 and 9, highlighting 6 with IC50 values of 33.3 µM on AA, 69.2 µM on AG and 164.4 µM on PL. Enzymatic kinetics and molecular docking studies showed that the bioactive xanthones are mainly competitive inhibitors on AA, mixed inhibitors on AG and non-competitive inhibitors on PL. The molecular coupling study established that the presence of methoxy, hydroxyl and carbonyl groups are important in the activity and interaction of polyfunctional xanthones, highlighting their importance depending on the mode of inhibition.

There are molecular structural features that are key to defining the agonist or antagonist activity on LasR, RhlR and PqsR transcription factors, associated with quorum sensing in Pseudomonas aeruginosa .

Introducción: la enfermedad de Chagas es endémica de las zonas tropicales de América Latina y presenta una importante prevalencia, sin embargo, existen pocos tratamientos disponibles en el mercado por lo que la búsqueda de moléculas con potencial farmacológico que actúen en el parásito Trypanosoma cruzi, causante de la enfermedad, es necesaria considerando las graves complicaciones. Objetivo: evaluar las potenciales proteínas blanco, disponibles en la base de datos de PDB conside-rando como parámetro inicial, la similitud con proteínas humanas e identificar potenciales inhibidores del blanco elegido por medio de acoplamiento molecular. Metodología: se realizó una evaluación de las proteínas del parásito por medio de alineamiento de secuencias y posteriormente un cribado virtual por acoplamiento molecular con bases de datos y recursos informáticos disponibles en el Centro de Cómputo Avanzado de la Universidad de Texas (TACC), y se evaluaron los mejores resultados en función de afinidad, farmacocinética y toxicidad. Resultados: el banco molecular elegido fue la dUTPasa. Posterior al cribado virtual se seleccio-naron 12 moléculas que presentan potencial inhibidor de estas, la4-{3-[3-(trifluoro-metil)fenil]isoxazol-5-il}pirimidin-2-amina es una de las moléculas con mejor perfil para convertirse en candidato en el tratamiento de la enfermedad de Chagas. Introduction: Chagas disease is endemic to the tropical areas of Latin America and has an important prevalence, however, there are few treatments available in the market, so the search for molecules with pharmacological potential that can act in the same way as the disease, it is necessary considering the serious complications.Aim: to evaluate the possible target proteins available in the PDB database, consid-ering the similarity with human proteins as an initial parameter and identify poten-tial inhibitors of the chosen target using molecular docking. Methodology: an eval-uation of the parasite proteins was carried out by means of sequence alignment and subsequently a virtual molecular coupling screening was performed with databases and computer resources available at Centro de Cómputo Avanzado de Universidad de Texas (TACC), and the best results were evaluated based on affinity, pharmacoki-netics, and toxicity. Results: the molecular target chosen was the dUTPase. After virtual screening, 12 moles showing inhibitory potential were selected of these, 4- {3- [3- (trifluoromethyl) phenyl] isoxazole-5-yl} pyrimidine-2-amine is one of the mole-cules with the best profile to become a candidate in the treatment of Chagas disease Introdução: a doença de Chagas é endêmica das áreas tropicais da América Latina e possui importante prevalência, porém, poucos são os tratamentos disponíveis no mercado, por isso a busca por moléculas com potencial farmacológico que possam atuar da mesma forma que a doença, é necessário considerando as complicações graves. Objetivo: avaliar as possíveis proteínas-alvo disponíveis na base de dados do PDB, considerando a similaridade com proteínas humanas como parâmetro inicial e iden-tificação de potenciais inibidores do alvo escolhido por meio de acoplamento mole-cular.. Metodologia: uma avaliação das proteínas do parasita foi realizada por meio de alinhamento de sequências e posteriormente foi realizada uma triagem de acopla-mento molecular virtual com bancos de dados e recursos computacionais disponíveis no Centro de Cómputo Avanzado de Universidad de Texas (TACC), e os melhores resultados foram avaliados com base na afinidade, farmacocinética e toxicidade. Resul-tados: o alvo molecular escolhido foi a dUTPase. Após a triagem virtual, 12 moles mostrando potencial inibitório foram selecionados destes, 4- {3- [3- (trifluorometil) fenil] isoxazol-5-il} pirimidina-2-amina é uma das moléculas com o melhor perfil para se tornar um candidato no tratamento da doença de Chagas

Among the compounds of natural origin, diterpenes have proved useful as drugs for the treatment of cancer. Marine organisms, such as soft corals and algae, are a promising source of diterpenes, being a rich and unexplored source of cytotoxic agents. This study evaluated a library of 32 natural and semisynthetic marine diterpenes, including briarane, cembrane, and dolabellane nuclei, with the aim of determining their cytotoxicity against three human cancer cell lines (A549, MCF7, and PC3). The three most active compounds were submitted to a flow cytometry analysis in order to determine induction of apoptosis against the A549 cell line. An NMR analysis was conducted to determine and evaluate the interactions between active diterpenes and tubulin. These interactions were characterized by a computational study using molecular docking and MD simulations. With these results, two cembrane and one chlorinated briarane diterpenes were active against the three human cancer cell lines, induced apoptosis in the A549 cell line, and showed interactions with tubulin preferably at the taxane‐binding site. This study is a starting point for the identification and optimization of the marine diterpenes selected for better antitumor activities. It also highlights the power of integrating NMR studies, computational predictions, and in vitro assays in the search for compounds with antitumor activity.