Synthesis of Pyrrolo[3,4-b]pyridin-5-ones via Ugi-Zhu Reaction and In Vitro-In Silico Studies against Breast Carcinoma.

An Ugi-Zhu three-component reaction (UZ-3CR) coupled in a one-pot manner to a cascade process (N-acylation/aza Diels-Alder cycloaddition/decarboxylation/dehydration) was performed to synthesize a series of pyrrolo[3,4-b]pyridin-5-ones in 20% to 92% overall yields using ytterbium triflate as a catalyst, toluene as a solvent, and microwaves as a heat source. The synthesized molecules were evaluated in vitro against breast cancer cell lines MDA-MB-231 and MCF-7, finding that compound 1f, at a concentration of 6.25 µM, exhibited a potential cytotoxic effect. Then, to understand the interactions between synthesized compounds and the main proteins related to the cancer cell lines, docking studies were performed on the serine/threonine kinase 1 (AKT1) and Orexetine type 2 receptor (Ox2R), finding moderate to strong binding energies, which matched accurately with the in vitro results. Additionally, molecular dynamics were performed between proteins related to the studied cell lines and the three best ligands.

Gene as a dynamical notion: An extensive and integrative vision. Redefining the gene concept, from traditional to genic-interaction, as a new dynamical version.

The current concept of gene has been very useful during the 20th and 21st centuries. However, recent advances in molecular biology and bioinformatics, which have further diversified the functional and adaptive profile of genetic information and its integration with cell physiology and environmental response, have contributed to focusing on additional new gene properties besides the traditional definition. Considering the inherent complexity of gene expression, whose adaptive objective must be referred to the Tortoise-Hare model, in which two tendencies converge, one focused on rapid adaptation to achieve survival, and the other that prevents an over-adaptation effect. In this context, a revision of the gene concept must be made, which must include these new mechanisms and approaches. In this paper, we propose a new conception of the idea of a gene that moves from a static and defined version of hereditary information to a dynamic idea that preponderates gene interaction (circumscribed to that established between protein-protein, protein-nucleic acid, and nucleic acid-nucleic acid) and the selection it exerts, as the irreducible element that works in a coordinated way in a genomic regulatory network (GRN).

Atomistic mechanism of leptin and leptin-receptor association.

The leptin-leptin receptor complex is at the very core of energy homeostasis and immune system regulation, among many other functions. In this work, we built homology models of leptin and the leptin binding domain (LBD) of the receptor from humans and mice. Docking analyses were used to obtain the coordinates of the native leptin-LBD complexes and a mixed heterodimer formed by human leptin and mouse LBD. Molecular dynamics (MD) simulations were performed using all models (monomers and heterodimers) as initial coordinates and the GROMACS program. The overall structural and dynamical behaviors are similar for the three complexes. Upon MD simulations, several new interactions appear. In particular, hydrophobic interactions, with more than 90% persistence, seem to be the most relevant for the stability of the dimers, as well as the pair formed by Asp85Lep and Arg468LBD. This in silico analysis provides structural and dynamical information, at the atomistic level, about the mechanism of leptin-LBD complex formation and leptin receptor activation. This knowledge might be used in the rational drug design of therapeutics to modulate leptin signaling.Communicated by Ramaswamy H. Sarma.

The Resilience of Pseudomonas aeruginosa to Antibiotics and the Designing of Antimicrobial Peptides to Overcome Microbial Resistance.

Pseudomonas aeruginosa (P. aeruginosa) is a bacterium of medical concern known for its potential to persist in diverse environments due to its metabolic capacity. Its survival ability is linked to its relatively large genome of 5.5-7 Mbp, from which several genes are employed in overcoming conventional antibiotic treatments and promoting resistance. The worldwide prevalence of antibiotic-resistant clones of P. aeruginosa necessitates novel approaches to researching their multiple resistance mechanisms, such as the use of antimicrobial peptides (AMPs). In this review, we briefly discuss the epidemiology of the resistant strains of P. aeruginosa and then describe their resistance mechanisms. Next, we explain the biology of AMPs, enlist the present database platforms that describe AMPs, and discuss their usefulness and limitations in treating P. aeruginosa strains. Finally, we present 13 AMPs with theoretical action against P. aeruginosa, all of which we evaluated in silico in this work. Our results suggest that the AMPs we evaluated have a carpet-like mode of action with a membranolytic function in Gram-positive and Gramnegative bacteria, with a clear potential of synthesis for in vitro evaluation.

Brazilin: Biological activities and therapeutic potential in chronic degenerative diseases and cancer.

Caesalpinia sappan and Haematoxylum brasiletto belong to the Fabaceae family, predominantly distributed in Southeast Asia and America. The isoflavonoid brazilin has been identified from the bark and heartwood of these plants. This review summarizes the studies describing the biological activities of these plants and brazilin. Mainly, brazilin protects cells from oxidative stress, shows anti-inflammatory and antibacterial properties, and hypoglycemic effect. In addition, it has a biological impact on various pathologies such as Alzheimer's disease, Parkinson's disease, fibrillogenesis, and osteoarthritis. Interestingly, most of the antecedents are related to the anticancer effect of brazilin. In several cancers such as osteosarcoma, neuroblastoma, multiple myeloma, glioblastoma, bladder, melanoma, breast, tongue, colon, cervical, head, and neck squamous cell carcinoma, brazilin induces autophagy by increasing the levels of the LC3-II protein. Furthermore, it inhibits cell proliferation and induces apoptosis through increased expression of Bcl-2, Bcl-XL, p21, p27, activation of caspase-3 and -7, and the cleavage of PARP and inhibiting the expression of Bax. In addition, it blocks the expression of JNK and regulates the nuclear translocation of Nrf2. Together, these data positions brazilin as a compound of natural origin with multiple bioactivities and therapeutic potential in various chronic degenerative diseases and cancer.

Molecular dynamics of the histamine H3 membrane receptor reveals different mechanisms of GPCR signal transduction.

In this work, we studied the mechanisms of classical activation and inactivation of signal transduction by the histamine H3 receptor, a 7-helix transmembrane bundle G-Protein Coupled Receptor through long-time-scale atomistic molecular dynamics simulations of the receptor embedded in a hydrated double layer of dipalmitoyl phosphatidyl choline, a zwitterionic polysaturated ordered lipid. Three systems were prepared: the apo receptor, representing the constitutively active receptor; and two holo-receptors-the receptor coupled to the antagonist/inverse agonist ciproxifan, representing the inactive state of the receptor, and the receptor coupled to the endogenous agonist histamine and representing the active state of the receptor. An extensive analysis of the simulation showed that the three states of H3R present significant structural and dynamical differences as well as a complex behavior given that the measured properties interact in multiple and interdependent ways. In addition, the simulations described an unexpected escape of histamine from the orthosteric binding site, in agreement with the experimental modest affinities and rapid off-rates of agonists.

In silico Design of Laccase Thermostable Mutants From Lacc 6 of Pleurotus Ostreatus.

Fungal laccase enzymes have a great biotechnological potential for bioremediation processes due to their ability to degrade compounds such as ρ-diphenol, aminophenols, polyphenols, polyamines, and aryldiamines. These enzymes have activity at different pH and temperature values, however, high temperatures can cause partial or total loss of enzymatic activity, so it is appropriate to do research to modify their secondary and/or tertiary structure to make them more resistant to extreme temperature conditions. In silico, a structure of the Lacc 6 enzyme of Pleurotus ostreatus was constructed using a laccase of Trametes versicolor as a template. From this structure, 16 mutants with possible resistance at high temperature due to ionic interactions, salt bridges and disulfide bonds were also obtained in silico. It was determined that 12 mutants called 4-DB, 3-DB, D233C-T310C, F468P, 3-SB, L132T, N79D, N372D, P203C, P203V, T147E, and W85F, presented the lowest thermodynamic energy. Based on the previous criterion and determining the least flexibility in the protein structures, three mutants (4-DB, 3-DB, and P203C) were selected, which may present high stability at high temperatures without affecting their active site. The obtained results allow the understanding of the molecular base that increase the structural stability of the enzyme Lacc 6 of Pleurotus ostreatus, achieving the in silico generation of mutants, which could have activity at high temperatures.