The absence of adequate force field (FF) parameters to describe certain metallic complexes makes new and deeper analyses impossible. In this context, after a group of researchers developed and validated an AMBER FF for a platinum complex (PC) conjugated with AHBT, new possibilities emerged. Thus, in this work, we propose an improved path to obtain NMR spectroscopic parameters, starting from a specific FF for PC, allowing to obtain more reliable information and a longer simulation time. Initially, a docking study was carried out between a PC and PI3K enzyme, aiming to find the most favorable orientation and, from this pose, to carry out a simulation of classical molecular dynamics (MD) with an explicit solvent and simulation time of 50 ns. To explore a new PC environment, a second MD simulation was performed only between the complex and water molecules, under the same conditions as the first MD. After the results of the two MDs, we proposed strategies to select the best amino acid residues (first MD) and water molecules (second MD) through the analyses of hydrogen bonds and minimum distance distribution functions (MDDFs), respectively. In addition, we also selected the best frames from the two MDs through the OWSCA algorithm. From these resources, it was possible to reduce the amount and computational cost of subsequent quantum calculations. Thus, we performed NMR calculations in two chemical environments, enzymatic and aqueous, with theory level GIAO–PBEPBE/NMR-DKH. So, from a strategic path, we were able to obtain more reliable chemical shifts and, therefore, propose safer spectroscopic probes, showing a large difference between the values of chemical shifts in the enzymatic and aqueous environments.

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.

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.

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.