Vanadium complex as a potential modulator of the autophagic mechanism through proteins PI3K and ULK1: development, validation and biological implications of a specific force field for [VO(bpy)2Cl].

The modulation of autophagy has been presented as a very useful strategy in anticancer treatments. In this sense, the vanadium complex (VC) bis(2,2'-bipyridine)chlorooxovanadium(IV), [VO(bpy)2Cl], is known for its ability to induce autophagy in triple-negative breast cancer cells (TNBC). An excellent resource to investigate the role of VC in the induction of autophagy is to make use of Molecular Dynamics (MD) simulations. However, until now, the scarcity of force field parameters for the VC prevented a reliable analysis. The autophagy signaling pathway starts with the PI3K protein and ends with ULK1. Therefore, in the first stage of this work, we developed a new AMBER force field for the VC (VCFF) from a quantum structure, obtained by DFT calculations. In the second stage, the VCFF was validated through structural analyses. From this, it was possible to investigate, through docking and MD (200 ns), the performance of the PI3K-VC and ULK1-VC systems (third stage). The analyses of this last stage involved RMSD, hydrogen bonds, RMSF and two pathways for the modulation of autophagy. In general, this work fills in the absence of force field parameters (FF) for VC by proposing an efficient and new FF, in addition to investigating, at the molecular level, how VC is able to induce autophagy in TNBC cells. This study encourages new parameterizations of metallic complexes and contributes to the understanding of the duality of autophagic processes.Communicated by Ramaswamy H. Sarma.

Evaluation of autophagy inhibition to combat cancer: (vanadium complex)-protein interactions, parameterization, and validation of a new force field.

Autophagy has drawn attention from the scientific community, mainly because of its significant advantages over chemotherapeutic processes. One of these advantages is its direct action on cancer cells, avoiding possible side effects, unlike chemotherapy, which reaches tumor cells and affects healthy cells in the body, leading to a great loss in the quality of life of patients. In this way, it is known that vanadium complex (VC) [VO(oda)(phen)] has proven inhibition effect on autophagy process in pancreatic cancer cells. Keeping that in mind, molecular dynamics (MD) simulations can be considered excellent strategies to investigate the interaction of metal complexes and their biological targets. However, simulations of this type are strongly dependent on the appropriate choice of force field (FF). Therefore, this work proposes the development of AMBER FF parameters for VC, having a minimum energy structure as a starting point, obtained through DFT calculations with B3LYP/def2-TZVP level of theory plus ECP for the vanadium atom. An MD simulation in vacuum was performed to validate the developed FF. From the structural analyses, satisfying values of VC bond lengths and angles were obtained, where a good agreement with the experimental data and the quantum reference was found. The RMSD analysis showed an average of only 0.3%. Finally, we performed docking and MD (120 ns) simulations with explicit solvent between VC and PI3K. Overall, our findings encourage new parameterizations of metal complexes with significant biological applications, as well as allow to contribute to the elucidation of the complex process of autophagy.

Exploring electronic, structural and dynamics parameters of phenylbenzothiazole complexes with Mn2+, Cu2+ and Zn2+ for designing new magnetic resonance imaging (MRI) probes: congruence between computation and spectroscopic data.

Cancer is one of the leading causes of human death worldwide, being one of the most serious problems faced by mankind. For the diagnosis, Magnetic Resonance Imaging (MRI), through effective contrast agents (Cas), has greatly helped in the diagnosis at the initial stages. However, it is necessary to include new compounds more effective and selective for cancer diagnosis. The complexes with Mn2+, Cu2+ and Zn2+ have received great attention due to their applications as CAs for MRI. Those materials can shorten the T2 and T2* transverse relaxation times. Thus, the representative structures for hyperfine coupling constants (HFCCs) were selected from docking results by frequency of occupancy calculations. From the Multivariate Analysis to obtain the PCA graphs in the choice of a representative conformations. it is possible to notice that the variable energy does not present a high correlation with the other variables, and structural factors, such as the spatial positions of the metal atoms, seem to be important in the reactivity of the complexes. Structural factors, such as the spatial positions of the metal atoms, seem to be important in the reactivity of the complexes. Theoretical findings suggest that the compounds are capable of increasing the Aiso values of the water molecules, but the complex [Zn(H2O)(NNO)] shows a greater influence, being more sensitive to the Electron paramagnetic resonance parameters than the complexes [CuCl(H2O)NNO] and [MnCl2(H2O)(NNO)] with the explicit solvent and the enzyme. MRI contrast agents have generated various problems due to their high toxicity. In this perspective, this compound may be a promising alternative for transporting the CAs into diseased tissue.Communicated by Ramaswamy H. Sarma.

Insights into the value of statistical models, solvent, and relativistic effects for investigating Re complexes of 2-(4'-aminophenyl)benzothiazole: a potential spectroscopic probe.

Cancer affects a major part of the worldwide population, and, to minimize deaths, the diagnosis in the early stages of the disease is fundamental. Thus, to improve diagnosis and treatment new potential spectroscopic probes are crucial. Benzothiazole derivates present antitumor properties and are highly selective and interact strongly with the enzyme phosphoinositide 3-kinase (PI3K), which was associated with cell proliferation and breast cancer cells. In this paper, the rhenium shielding tensors (187Re(σ)) and hydrogen and carbon chemical shifts (1H(δ) and 13C(δ)) of the Re(CO)3(NNO) complex conjugated with 2-(4'-aminophenyl)benzothiazole (ReABT) were evaluated. A statistical HCA model was used to analyze the best DFT protocol to compute σ and δ values and to evaluate the relativistic effects, both in the basis set and Hamiltonian as well as the functionals M06L or PBE0. The best protocol was applied to obtain 187Re(σ) of the ReABT complex in different environments (gas phase, solution, and in the active site of the PI3K enzyme). The results point out that 187Re(σ) values of the ReABT complex change significantly when the complex is docked in the PI3K enzyme.

Value of Contrast-enhanced Magnetic Resonance Imaging (MRI) in the Diagnosis of Breast Cancer.

This review article aims to address the main features of breast cancer. Thus, the general aspects of this disease have been shown since the first evidence of breast cancer in the world until the numbers today. In this way, there are some ways to prevent breast cancer, such as the woman's lifestyle (healthy eating habits and physical activities) that helps to reduce the incidence of this anomaly. The first noticeable symptom of this anomaly is typically a lump that feels different from the rest of the breast tissue. More than 80% of breast cancer are discovered when the woman feels a lump being present and about 90% of the cases, the cancer is noticed by the woman herself. Currently, the most used method for the detection of cancer and other injuries is the Magnetic Resonance Imaging (MRI) technique. This technique has been shown to be very effective, however, for a better visualization of the images, Contrast Agents (CAs) are used, which are paramagnetic compounds capable of increasing the relaxation of the hydrogen atoms of the water molecules present in the body tissues. The most used CAs are Gd3+ complexes, although they are very efficient, they are toxic to the organism. Thus, new contrast agents have been studied to replace Gd3+ complexes; we can mention iron oxides as a promising substitute.

Interactions of cantharidin-like inhibitors with human protein phosphatase-5 in a Mg2+ system: molecular dynamics and quantum calculations.

The serine/threonine protein phosphatase type 5 (PP5) is a promising target for designing new antitumor drugs. This enzyme is a member of the PPP phosphatases gene family, which catalyzes a dephosphorylation reaction: a regulatory process in the signal transduction pathway that controls various biological processes. The aim of this work is to study and compare the inhibition of PP5 by ten cantharidin-like inhibitors in order to bring about contributions relevant to the better comprehension of their inhibitory activity. In this theoretical investigation, we used molecular dynamics techniques to understand the role of key interactions that occur in the protein active site; QM calculations were employed to study the interaction mode of these inhibitors in the enzyme. In addition, atoms in molecules (AIM) calculations were carried out to characterize the chemical bonds among the atoms involved and investigate the orbital interactions with their respective energy values. The obtained results suggest that the Arg275, Asn303, His304, His352, Arg400, His427, Glu428, Val429, Tyr451, and Phe446 residues favorably contribute to the interactions between inhibitors and PP5. However, the Asp271 and Asp244 amino acid residues do not favor such interactions for some inhibitors. Through the QM calculations, we can suggest that the reactional energy of the coordination mechanism of these inhibitors in the PP5 active site is quite important and is responsible for the inhibitory activity. The AIM technique employed in this work was essential to get a better comprehension of the transition states acquired from the mechanism simulation. This work offers insights of how cantharidin-like inhibitors interact with human PP5, potentially allowing the design of more specific and even less cytotoxic drugs for cancer treatments. Graphical Abstract Interactions of cantharidin-like inhibitors with human protein phosphatase-5 in a Mg2+ system.

Synthesis, antiproliferative activities, and computational evaluation of novel isocoumarin and 3,4-dihydroisocoumarin derivatives.

A series of novel isocoumarin derivatives were synthesized using Castro-Stephens cross-coupling. Moreover, novel 3,4-dihydroisocoumarin derivatives were obtained by catalytic hydrogenation of the corresponding isocoumarin precursors. The antiproliferative activity of all compounds was evaluated in vitro in different tumor cells. Furthermore, docking calculations were performed for the kallikrein 5 (KLK5) active site to predict the possible mechanism of action of this series of compounds. Theoretical findings indicate that the 3,4-dihydroisocoumarin derivative 10a forms hydrogen bonds with Ser190 and Gln192 residues of KLK5. This derivative was the most active compound in the series with potent antiproliferative activity and high selectivity index (SI > 378.79) against breast cancer cells (MCF-7, GI50 = 0.66 µg mL(-1)). This compound represents a promising matrix for developing new antiproliferative agents.

QSAR analysis of nicotinamidic compounds and design of potential Bruton's tyrosine kinase (Btk) inhibitors.

Bruton's tyrosine kinase (Btk) is an important enzyme in B-lymphocyte development and differentiation. Furthermore, Btk expression is considered essential for the proliferation and survival of these cells. Btk inhibition has become an attractive strategy for treating autoimmune diseases, B-cell leukemia, and lymphomas. With the objective of proposing new candidates for Btk inhibitors, we applied receptor-dependent four-dimensional quantitative structure-activity relationship (QSAR) methodology to a series of 96 nicotinamide analogs useful as Btk modulators. The QSAR models were developed using 71 compounds, the training set, and externally validated using 25 compounds, the test set. The conformations obtained by molecular dynamics simulation were overlapped in a virtual three-dimensional cubic box comprised of 2 and 5 Å cells, according to the six trial alignments. The models were generated by combining genetic function approximation and partial least squares regression technique. The analyses suggest that Model 1a yields the best results. The best equation shows [Formula: see text], r(2) = .743, RMSEC = .831, RMSECV = .879. Given the importance of the Tyr551, this residue could become a strategic target for the design of novel Btk inhibitors with improved potency. In addition, the good potency predicted for the proposed M2 compound indicates this compound as a potential Btk inhibitor candidate.

Synthesis and antiproliferative activity of 8-hydroxyquinoline derivatives containing a 1,2,3-triazole moiety.

Twelve novel 8-hydroxyquinoline derivatives were synthesized with good yields by performing copper-catalyzed Huisgen 1,3-dipolar cycloaddition ("click" reaction) between an 8-O-alkylated-quinoline containing a terminal alkyne and various aromatic or protected sugar azides. These compounds were evaluated in vitro for their antiproliferative activity on various cancer cell types. Protected sugar derivative 16 was the most active compound in the series, exhibiting potent antiproliferative activity and high selectivity toward ovarian cancer cells (OVCAR-03, GI50 < 0.25 µg mL(-1)); this derivative was more active than the reference drug doxorubicin (OVCAR-03, GI50 = 0.43 µg mL(-1)). In structure-activity relationship (SAR) studies, the physico-chemical parameters of the compounds were evaluated and docking calculations were performed for the α-glucosidase active site to predict the possible mechanism of action of this series of compounds.

QSAR and docking studies of HCV NS3 serine protease inhibitors.

Hepatitis C virus (HCV) is a Hepacivirus that causes chronic liver disease, leading to hepatocellular carcinoma, cirrhosis, and chronic hepatitis in about 3% of the world population. In this study, novel HCV NS3 serine protease inhibitors based on 93 boceprevir analogs were studied by QSAR analyses using thermodynamic, structural and topological descriptors, including E-state descriptors. Novel compounds were proposed using the QSAR models. Both models were highly predictive, with calibration, leave-one-out validation and external validation R2 of 0.66, 0.65 and 0.52, respectively. The most promising structures were docked into the HCV NS3 serine protease active site demonstrating, then, the high affinity of some new structures.