Taináh Martins Resende Santos

The mucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) is a key protein in the adaptive immune response system in humans. This protein is widely expressed in the human body and is related to nuclear factor-κB (NF-κB) signaling activation in response to T-cell receptors. Due to this, MALT1 is key in the regulation of inflammatory events in a variety of tissues, where its dysregulation is associated with several types of cancer, especially hematological cancers. In this sense, its relevance makes MALT1 a valuable target to treat many diseases, drawing the attention of many researchers with the aim of proposing new MALT1 inhibitors. However, there is a lack of literature describing its complex dynamical behavior and allosteric inhibition, which considerably hampers the computational design of new MALT1 allosteric inhibitors. In that regard, the present work investigated the complex conformational behavior of MALT1 protein during its allosteric inhibition. For this, biased molecular dynamics simulations, sophisticated machine learning techniques such as neural networks, and docking calculations were used. From the performed investigation, it was observed that through allosteric inhibition, Loop 1 and 3 movements were crucial to reduce the catalytic site cavity volume, keeping cysteine unavailable for substrate mimic binding. In addition, statistical information over the explored ensemble showed that the great majority of the inhibited conformations presented an unavailable catalytic cysteine for substrate binding. Hence, the presented results can be used as an objective criterion for the computational proposal of new MALT1 allosteric inhibitors. However, despite mouse MALT1 and human MALT1 presenting 93% homology, the generalization of the findings to human MALT1 protein should be taken with care, and the obtained results apply specifically to the mouse MALT1 construct.

Context The modulation of autophagy – inhibition or induction – has emerged as a promising strategy in cancer treatment, offering significant advantages over conventional chemotherapy. Previously, we demonstrated that the vanadium complex [VO(oda)(phen)] inhibits autophagy by activating the phosphoinositide 3-kinase gamma (PI3Kγ) protein. Given the therapeutic potential of autophagy modulation, we proposed structural modifications to this complex to achieve the opposite effect: autophagy activation by preventing PI3Kγ activation. In this context, this study aimed to perform structural modifications on the vanadium complex to elucidate and discuss new conformational implications and its role in the autophagic machinery. The AMBER force field (FF) was adapted for the modified vanadium complex (mVC), yielding excellent results in molecular dynamics (MD) simulations in vacuum, protein, and aqueous environments. The structural modifications successfully disrupted the interaction between [VO(oda)(phen)] and PI3Kγ, previously identified as a key factor in PI3Kγ activation. Consequently, PI3Kγ deactivation leads to a shift in the autophagy signaling pathway, promoting autophagy activation. Additionally, NMR calculations were performed to explore a novel role for mVC, broadening its potential applications. Methods MD simulations were conducted at 800 ns using the AMBER program, while Molegro Virtual Docker (MVD) was employed for docking simulations. Optimization calculations (B3LYP/def2-TZVP and LANL2DZ ECP for V) and NMR calculations (PBE/IGLO-II and Wachters + f for V) were performed using Gaussian 09. The key frames from the MD simulations were selected using the OWSCA algorithm. Ligand and protein performance were evaluated through RMSD, RMSF, and hydrogen bond analyses, applying cutoff distances of 3.5 Å and 30°.

Tropical beef has low marbling and variable intramuscular lipids, making the meat appear between dry and juicy due to the lack of intramuscular fat. The objective of this work is to obtain the 3D structure of bovine PPARγ and discover new compounds that activate it. The target sequence used showed high sequence identity with the human PPARγ protein model. Virtual screening and molecular docking identified compounds that activate human PPARγ. The docking parameters were validated through ROC curve and redocking, and a virtual screening resulted in 274 compounds for further research. After applying filters, 12 compounds showed better affinity with PPARγ and lower toxicity compared with the reference ligand. Compound 3 and Compound 4 showed favorable interactions with PPARγ in molecular dynamics simulations, raising expectations for the discovery of new activators.

Since 2020, the attention of the scientific community has been focused on the overwhelming COVID-19 pandemic, the infectious disease caused by the coronavirus that has affected populations worldwide. The alarming number of deaths and the severity of the symptoms have driven studies aimed at combating this disease. One of the key components in the development of this disease is the protein M^Pro, responsible for the replication and transcription of the virus, making it an excellent biological target in research efforts seeking an effective treatment for the disease. Furthermore, studies have shown that vanadium complexes, such as bis(N′,N′-dimethylbiguanide)oxovanadium (IV), VO(metf)₂∙H₂O, exhibit highly promising effects for the treatment of COVID-19. This molecule contains a ligand known as metformin, which also holds a prominent place as a potential agent in the treatment of this disease due to its antiviral properties. Therefore, an investigation into the interactions between these two systems (M^Pro+Vanadium Complex and M^Pro+Metformin) is pertinent given the significance of these two molecules. Thus, computational studies such as molecular docking and classical molecular dynamics are considered advantageous, assisting in this comparative study, as well as providing a deeper understanding of the interactions that occur within each of them.

Nerve agents are organophosphates (OPs) that act as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. After inhibition, a dealkylation reaction of the phosphorylated serine, known as the aging of AChE, can occur. When aged, reactivators of OP-inhibited AChE are no longer effective. Therefore, the realkylation of aged AChE may offer a pathway to reverse AChE aging. In this study, molecular modeling was conducted to propose new ligands as realkylators of aged AChE. We applied a methodology involving docking and quantum mechanics/molecular mechanics (QM/MM) calculations to evaluate the resurrection kinetic constants and ligand interactions with OP-aged AChE, comparing them to data found in the literature. The results obtained confirm that this method is suitable for predicting kinetic and thermodynamic parameters of ligands, which can be useful in the design and selection of new and more effective ligands for AChE realkylation.

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.

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. Graphical abstract

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.