Approximately 50 million people worldwide have been affected by dementia. The consequence of this syndrome is a decline in cognitive function beyond what is normally expected during aging [1]. The estimated global cost of dementia exceeds $1.3 trillion annually and is expected to increase to $2.8 trillion by 2030 [2]. Besides the economic impact, this neurodegenerative condition can aggressively affect the patient and their family from a physical and psychological point of view [3].

One of the most recurrent conditions associated with dementia is the so-called Alzheimer's disease (AD), an extremely complex disease that has been studied very closely by the scientific community in the search of further clarification of its pathogenesis [4]. AD is known for having three stages, where in the first stage, the patient can experience memory lapses but may function independently. For stage two, communicative and cognitive skills are affected. The symptoms become progressively more intense throughout the third stage, the nerve cells in the brain are damaged and the individual loses their ability to respond to the environment [5].

Different hypotheses have attempted to explain what causes such severe condition. The amyloid cascade hypothesis is considered one of the main premises that has been the subject of study for more than 25 years [3,6]. However, recently evidence suggests that the inhibition of protein tyrosine phosphatase 1B (PTP1B) may potentially modulate several processes in the central nervous system, affecting the development of AD [7].

Tyrosine-protein phosphatase non-receptor type 1, also known as protein-tyrosine phosphatase 1B (PTP1B), is a negative regulator of the insulin signaling pathway, inducing insulin resistance [8]. PTP1B is also associated with conditions such as inflammation and obesity [9].

Moreover, PTP1B has been indicated as a modulator of the brain-derived neurotrophic factor (BDNF), a regulator of synaptic plasticity. Since brains affected by AD presents decreasing levels of BDNF, PTP1B is, in fact, considered a promising approach for potential treatment of AD [7]. Thus, it is possible to infer, based on such findings, that PTP1B can be considered a bridge between AD and T2DM.

Accordingly, antidiabetic drugs have been explored as promising treatment strategies to approach AD, based on their neuroprotective mechanisms, showing improvement of cognitive ability and spatial memory [10,11]. Furthermore, preclinical, and clinical trials show encouraging results towards neurodegeneration and need further clarification [12].

Among the potential candidates, insulin, metformin, and a variety of metal complexes, such as platinum, copper, cobalt, and vanadium, have been under investigation [12,13]. Particularly, among the vanadium complexes under study, bis(maltolato)oxovanadium (IV) (BMOV) (Fig. 1a) is considered a benchmark for antidiabetic agents, having the best effect on inhibiting PTP1B activity, and enhancing insulin receptor activation in vivo [14].

Although experimental techniques, such as X-ray crystallography, are essential to precisely describe the structure of a complex, a theoretical approach may contribute significantly by seeking to understand the structural, and chemical behavior of such complex, making possible the study of this potential agent against this neurodegenerative disease, based on therapeutic effects of BMOV [15].

Molecular Dynamics (MD) is an effective theoretical method that provides accurate description of systems in general, its results are highly dependent on a reliable parameterization of the force field (FF) and the attempt to model a chemical system described by force field can be very challenging. In addition, the choice of force fields is an essential step for the correct description of the system under study [[16], [17], [18], [19]].

Another important point to be addressed is the scarcity of parameters for metal centers, making this situation even more complex [17]. General force fields cannot be applicable or transferable to other systems due to different atom types that are not considered during the force field development [18]. Moreover, for metal-containing molecules, most of the general force fields predict the structure of complexes in an unreliable way [20]. Thus, a new Assisted Model Building with Energy Refinement (AMBER) force field for the vanadium complex BMOV is considered necessary. A recent work has explored the development of new parameters for a vanadium complex, VO(metf)2·H2O, where the results are excellent and encourage such investigation [21].

With that being said, the purpose of this work is to effectively obtain a set of parameters for this relevant BMOV (Fig. 1a) allowing further studies to provide a deeper understanding of the behavior of the system associated with AD and T2DM. The methodology used in this work involves developing and validating the new AMBER force field through classical MD simulations and comparison with experimental data and quantum reference.

Furthermore, in a second step, a case study was proposed to investigate the interactions between BMOV and PTP1B, where hydrogen bonds (HBonds) in the BMOV-PTP1B system were pointed out during the docking investigation and validated based on MD simulation (200 ns) in explicit solvent.