RESUMO

Early phase diagnosis of human diseases has still been a challenge in the medicinal field, and one of the efficient non-invasive techniques that is vastly used for this purpose is magnetic resonance imaging (MRI). MRI is able to detect a wide range of diseases and conditions, including nervous system disorders and cancer, and uses the principles of NMR relaxation to generate detailed internal images of the body. For such investigation, different metal complexes have been studied as potential MRI contrast agents. With this in mind, this work aims to investigate two systems containing the vanadium complexes [VO(metf)2]·H2O (VC1) and [VO(bpy)2Cl]+ (VC2), being metformin and bipyridine ligands of the respective complexes, with the biological targets AMPK and ULK1. These biomolecules are involved in the progression of Alzheimer's disease and triple-negative breast cancer, respectively, and may act as promising spectroscopic probes for detection of these diseases. To initially evaluate the behavior of the studied ligands within the aforementioned protein active sites and aqueous environment, four classical molecular dynamics (MD) simulations including VC1 + H2O (1), VC2 + H2O (2), VC1 + AMPK + H2O (3), and VC2 + ULK1 + H2O (4) were performed. From this, it was obtained that for both systems containing VCs and water only, the theoretical calculations implied a higher efficiency when compared with DOTAREM, a famous commercially available contrast agent for MRI. This result is maintained when evaluating the system containing VC1 + AMPK + H2O. Nevertheless, for the system VC2 + ULK1 + H2O, there was observed a decrease in the vanadium complex efficiency due to the presence of a relevant steric hindrance. Despite that, due to the nature of the interaction between VC2 and ULK1, and the nature of its ligands, the study gives an insight that some modifications on VC2 structure might improve its efficiency as an MRI probe.

RESUMO

Coronavirus is caused by the SARS-CoV-2 virus has shown rapid proliferation and scarcity of treatments with proven effectiveness. In this way, we simulated the hospitalization of carbon nanospheres, with external active sites of the SARS-CoV-2 virus (M-Pro, S-Gly and E-Pro), which can be adsorbed or inactivated when interacting with the nanospheres. The computational procedures performed in this work were developed with the SwissDock server for molecular docking and the GROMACS software for molecular dynamics, making it possible to extract relevant data on affinity energy, distance between molecules, free Gibbs energy and mean square deviation of atomic positions, surface area accessible to solvents. Molecular docking indicates that all ligands have an affinity for the receptor's active sites. The nanospheres interact favorably with all proteins, showing promising results, especially C60, which presented the best affinity energy and RMSD values ​​for all protein macromolecules investigated. The C60 with E-Pro exhibited the highest affinity energy of -9.361 kcal/mol, demonstrating stability in both molecular docking and molecular dynamics simulations. Our RMSD calculations indicated that the nanospheres remained predominantly stable, fluctuating within a range of 2 to 3 Å. Additionally, the analysis of other structures yielded promising results that hold potential for application in other proteases.Communicated by Ramaswamy H. Sarma.

RESUMO

BACKGROUND: The quantitative structure-activity relationship is an analysis method that can be applied for designing new molecules. In 1997, Hopfinger and coworkers developed the 4DQSAR methodology aiming to eliminate the question of which conformation to use in a QSAR study. In this work, the 4D-QSAR methodology was used to quantitatively determine the influence of structural descriptors on the activity of aryl pyrimidine derivatives as inhibitors of the TGF-ß1 receptor. The members of the TGF-ß subfamily are interesting molecular targets, since they play an important function in the growth and development of cell cellular including proliferation, apoptosis, differentiation, Epithelial-Mesenchymal Transition (EMT), and migration. In late stages, TGF-ß exerts tumor-promoting effects, increasing tumor invasiveness, and metastasis. Therefore, TGF-ß is an attractive target for cancer therapy. OBJECTIVE: The major goal of the current research is to develop 4D-QSAR models aiming to propose new structures of aryl pyrimidine derivatives. MATERIALS AND METHODS: Molecular dynamics simulation was carried out to generate the conformational ensemble profile of a data set with aryl pyrimidine derivatives. The conformations were overlaid into a three-dimensional cubic box, according to the three-ordered atom alignment. The occupation of the grid cells by the interaction of pharmacophore elements provides the Grid Cell Occupancy Descriptors (GCOD), the dependent variables used to build the 4D-QSAR models. The best models were validated (internal and external validation) using several statistical parameters. Docking molecular studies were performed to better understand the binding mode of pyrimidine derivatives inside the TGF-ß active site. RESULTS: The 4D-QSAR model presented seven descriptors and acceptable statistical parameters (R2 = 0.89, q2 = 0.68, R2 pred = 0.65, r2 m = 0.55, R2 P = 0.68 and R2 rand = 0.21) besides pharmacophores groups important for the activity of these compounds. The molecular docking studies helped to understand the pharmacophoric groups and proposed substituents that increase the potency of aryl pyrimidine derivatives. CONCLUSION: The best QSAR model showed adequate statistical parameters that ensure their fitness, robustness, and predictivity. Structural modifications were assessed, and five new structures were proposed as candidates for a drug for cancer treatment.

Assuntos

RESUMO

Autism Spectrum Disorder (ASD) is a disorder with different etiologies and poor elucidation, characterized by changes in social and cognitive skills. ASD impacts a large number of people in the world. Surprisingly, in spite of its great importance, just modest progress has been achieved towards comprehending this pathology and designing new therapies. The molecular dysfunctions observed in people with autism are evidenced by the interference in the synthesis of synaptic proteins, which impairs their development and plasticity, leading to characteristics of individuals with ASD. The present work investigates the mTOR pathway and the proteins related to its regulation and neurological functioning. The path of protein synthesis and translation is promising to treat various disorders and its elucidation may, for example, result in drugs that facilitate the diagnosis and broaden the range of treatments, improving the quality of life of ASD patients.

Assuntos

RESUMO

Assembled together with the most common qubits used in nuclear resonance magnetic (NMR) quantum computation experiments, spin-1/2 nuclei, such as 113Cd, 199Hg, 125Te, and 77Se, could leverage the prospective scalable quantum computer architectures, enabling many and heteronuclear qubits for NMR quantum information processing (QIP) implementations. A computational design strategy for prescreening recently synthesized complexes of cadmium, mercury, tellurium, selenium, and phosphorus (called MRE complexes) as suitable qubit molecules for NMR QIP is reported. Chemical shifts and spin-spin coupling constants (SSCCs) in five MRE complexes were examined using the spin-orbit zeroth order regular approximation (ZORA) at the density functional theory level and the four-component relativistic Dirac-Kohn-Sham approach. In particular, the influence of different conformers, basis sets, exchange-correlation functionals, and methods to treat the relativistic as well as solvent effects were studied. The differences in the chemical shifts and SSCCs between different low energy conformers of the studied complexes were found to be very small. The TZ2P basis set was found to be the optimum choice for the studied chemical shifts, while the TZ2P-J basis set was the best for the couplings studied in this work. The PBE0 exchange-correlation functional exhibited the best performance for the studied MRE complexes. The addition of solvent effects has not improved on the gas phase results in comparison to the experiment, with the exception of the phosphorus chemical shift. The use of MRE complexes as qubit molecules for NMR QIP could face the challenges in single qubit control and multiqubit operations. They exhibit chemical shifts appropriately dispersed, allowing qubit addressability and exceptionally large spin-spin couplings, which could reduce the time of quantum gate operations and likely preserve the coherence.

RESUMO

FLT3 and dual Aurora B/FLT3 inhibitors have shown relevance in the search for promising new anticancer compounds, mainly for acute myeloid leukemia (AML). This study was designed to investigate the interactions between human FLT3 in the kinase domain with several indolin-2-one derivatives, structurally similar to Sunitinib. Molegro Virtual Docker (MVD) software was utilized in docking analyses. The predicted model of the training group, considering nineteen amino acid residues, performed in Chemoface, achieved an R2 of 0.82, suggesting that the binding conformations of the ligands with FLT3 are reasonable, and the data can be used to predict the interaction energy of other FLT3 inhibitors with similar molecular patterns. The MolDock Score for energy for compound 1 showed more stable interaction energy (-233.25 kcal mol-1) than the other inhibitors studied, while Sunitinib presented as one of the least stable (-160.94 kcal mol-1). Compounds IAF70, IAF72, IAF75, IAF80, IAF84, and IAF88 can be highlighted as promising derivatives for synthesis and biological evaluation against FLT3. Furthermore, IAF79 can be considered to be a promising dual Aurora B/FLT3 inhibitor, and its molecular pattern can be exploited synthetically to search for new indolin-2-one derivatives that may become drugs used in the treatment of cancers, including AML.

Assuntos

RESUMO

In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition-elimination steps, starting with a nucleophile bimolecular substitution (SN2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE.

Assuntos

RESUMO

7-methoxytacrine-4-pyridinealdoxime (7-MEOTA-4-PA, named hybrid 5C) is a compound formerly synthesized and evaluated in vitro, together with 4-pyridine aldoxime (4-PA) and commercial reactivators of acetylcholinesterase (AChE). This compound was designed with the purpose of being a prophylactic reactivator, capable of interacting with different subdomains of the active site of AChE. To investigate these interactions, theoretical results from docking were first compared with experimental data of hybrid 5C, 4-PA, and two commercial oximes, on the reactivation of human AChE (HssAChE) inhibited by VX. Then, further docking studies, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, were carried out to investigate reactivation performances, considering the near attack conformation (NAC) approach, prior to the nucleophilic substitution mechanism. Our results helped to elucidate the interactions of such molecules with the different subdomains of the active site of HssAChE. Additionally, NAC poses of each oxime were suggested for further theoretical studies on the reactivation reaction.

Assuntos

RESUMO

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.

Assuntos

RESUMO

Malaria is a disease caused by protozoan parasites of the genus Plasmodium that affects millions of people worldwide. In recent years there have been parasite resistances to several drugs, including the first-line antimalarial treatment. With the aim of proposing new drugs candidates for the treatment of disease, Quantitative Structure⁻Activity Relationship (QSAR) methodology was applied to 83 N-myristoyltransferase inhibitors, synthesized by Leatherbarrow et al. The QSAR models were developed using 63 compounds, the training set, and externally validated using 20 compounds, the test set. Ten different alignments for the two test sets were tested and the models were generated by the technique that combines genetic algorithms and partial least squares. The best model shows r² = 0.757, q²adjusted = 0.634, R²pred = 0.746, R²m = 0.716, ∆R²m = 0.133, R²p = 0.609, and R²r = 0.110. This work suggested a good correlation with the experimental results and allows the design of new potent N-myristoyltransferase inhibitors.

Assuntos

RESUMO

RESUMO Muitos compostos organofosforados (OP) são utilizados até hoje na agricultura como pesticidas e, infelizmente, como agentes de guerra química (ou agentes dos nervos) também. Os pesticidas organofosforados e os agentes dos nervos são moléculas extremamente tóxicas, uma vez que atuam como inibidores da enzima Acetilcolinesterase (AChE). O efeito mais preocupante da exposição a estes compostos é a toxicidade colinérgica aguda, ou seja, a perda de coordenação muscular. Uma vez que o indivíduo se contamina, o processo de intoxicação começa através da ligação do OP no sítio ativo da enzima AChE inativando-a. Os tratamentos atuais para pessoas expostas a baixas doses de OP podem ser realizados com atropina, oximas e benzodiazepínicos. Processos de remediação importantes envolvem o emprego de técnicas de biorremediação utilizando diferentes enzimas degradantes, como a Fosfotriesterase da Agrobacterium radiobacter e SMP-30. Devido ao elevado número de intoxicações anualmente, é crucial buscar métodos de tratamento mais potentes e eficazes, e nesta linha, as técnicas envolvendo biorremediação parecem ser bastante promissoras para este propósito.

ABSTRACT Many organophosphorus compounds (OP) are used until today in agriculture as pesticides and, unfortunately, they are used as chemical warfare agents (or nerve agents) as well. Organophosphorus pesticides and nerve agents are extremely toxic molecules, since they act as Acetylcholinesterase (AChE) inhibitors. The most worrying effect of the exposure to these compounds is the acute cholinergic toxicity, which is the loss of muscle coordination. Once one is contaminated, the intoxication process begins through the binding of the OP in the active site of the AChE enzyme inactivating it. Current treatments for people exposed to low doses of OP can be performed with atropine, oximes and benzodiazepines. Important remediation processes involve the employment of bioremediation techniques using different degrading enzymes, such as the Phosphotriesterase from Agrobacterium radiobacter and SMP-30. Due to the high number of intoxications annually, it is crucial to search for more potent and effective treatment methods, and in this line, the techniques involving bioremediation seem to be quite promising for this purpose.

RESUMO

In the present work, we propose to design drugs that target the enzyme dihydrofolate redutase (DHFR) as a means of a novel drug therapy against plague. Potential inhibitors of DHFR from Yersinia pestis (YpDHFR) were selected by virtual screening and subjected to docking, molecular dynamics (MD) simulations, and Poisson-Boltzmann surface area method, in order to evaluate their interactions in the active sites of YpDHFR and human DHFR (HssDHFR). The results suggested selectivity for three compounds that were further used to propose the structures of six new potential selective inhibitors for YpDHFR.

Assuntos

RESUMO

In this study, quantitative structure-activity relationship studies which make use of molecular dynamics trajectories were performed on a set of 54 glucokinase protein activators. The conformations obtained by molecular dynamics simulation were superimposed according to the twelve alignments tested in a virtual three-dimensional box comprised of 2 Å cells. The models were generated by the technique that combines genetic algorithms and partial least squares. The best alignment models generated with a determination coefficient (r(2)) between 0.674 and 0.743 and cross-validation (q(2)) between 0.509 and 0.610, indicating good predictive capacity. The 4D-QSAR models developed in this study suggest novel molecular regions to be explored in the search for better glucokinase activators.

Assuntos

RESUMO

The present work describes a simple integrated Quantum Mechanics/Molecular Mechanics method developed to study the reactivation steps by pralidoxime (2-PAM) of acetylcholinesterase (AChE) inhibited by the neurotoxic agent Tabun. The method was tested on an AChE model and showed to be able to corroborate most of the results obtained before, through a more complex and time-consuming methodology, proving to be suitable to this kind of mechanistic study at a lower computational cost.

Assuntos

RESUMO

Smallpox was one of the most devastating diseases in the human history and still represents a serious menace today due to its potential use by bioterrorists. Considering this threat and the non-existence of effective chemotherapy, we propose the enzyme thymidylate kinase from Variola virus (VarTMPK) as a potential target to the drug design against smallpox. We first built a homology model for VarTMPK and performed molecular docking studies on it in order to investigate the interactions with inhibitors of Vaccinia virus TMPK (VacTMPK). Subsequently, molecular dynamics (MD) simulations of these compounds inside VarTMPK and human TMPK (HssTMPK) were carried out in order to select the most promising and selective compounds as leads for the design of potential VarTMPK inhibitors. Results of the docking and MD simulations corroborated to each other, suggesting selectivity towards VarTMPK and, also, a good correlation with the experimental data.

Assuntos