SciForum MOL 2 NET Computational study of aromatic compounds inhibiting Trypanosoma cruzi glyceraldehyde 3-phosphate dehydrogenase

Chagas disease is caused by the protozoan Trypanosoma cruzi and is widely distributed throughout Latin America. Because it is a pathology neglected by the pharmaceutical industry and because existing drugs have low efficacy and several side effects, interest in new drugs has been increasing. Due to the necessity of the discovery of new structures, the objective of this work was to relate the biological activity of natural and semi-synthetic aromatic compounds, inhibitors of glyceraldehyde 3-phosphate dehydrogenase enzyme, with descriptors calculated by molecular modeling, such as HOMO-LUMO frontier orbitals, partition coefficient (LogP) and water solubility (LogS), in addition to performing a molecular docking study, in order to obtain a better molecular view of the interaction of the aromatic compounds with the active site of the enzyme. It was observed that the compounds involved in the study interacted attractively with the enzyme, in accordance with experimental studies, and had adequate solubility for good pharmacokinetics. It was also possible to relate the pharmacological activity of some compounds with the energy of the LUMO orbital. The study showed that the methodology used in this work can be used to understand the interaction of active compounds with their respective targets, saving time and resources. __________________________________________________________________________________


Introduction:
Chagas disease is an infectious process caused by the protozoan Trypanosoma cruzi, which in turn is transmitted to humans through triatomine insects commonly known as "barbers" [1][2][3].
A number of natural and synthetic compounds have been highlighted because they present high pharmacological activity against T. cruzi, through the inhibition of glyceraldehyde 3phosphate dehydrogenase (GAPDH), a glycolytic enzyme responsible for the conversion of glyceraldehyde-3-phosphate to 1,3 diphosphoglycerate and which has structural differences with respect to the human enzyme.
The infective forms of T. cruzi are dependent on the glycolytic pathway, which makes the enzyme a promising target for the creation of antichagasic drugs, since the inhibition of GAPDH will cause the inhibition of the T. cruzi glycolytic pathway [4,5].

Molecular Docking Study
The Results and Discussion:

Molecular Descriptors
In The results show that all the compounds involved in this work have adequate solubility for a good bioavailability, because it can be said that compounds with logS values between -1 and -5 present hydrophilicity required for aqueous solubility and lipophilicity to interact with hydrophobic surfaces [31].
In order to predict the electronic characteristics of compounds 1-6, the boundary molecular orbitals (HOMO and LUMO) were calculated by the semi-empirical quantum method PM7 (Table 2) It can be observed that triliroside, the compound with the highest inhibitory activity of the enzyme GAPDH, showed the lowest energy of LUMO orbital, which indicates that its stability to the active site can occur by the interaction of the LUMO of the triliroside with HOMO orbital of the enzyme.

Docking Molecular
Table 3 shows the results obtained through the docking study between compounds 1-6 with the enzyme glyceraldehyde 3-phosphate dehydrogenase [33].It can be seen that all compounds 1-6 interacted with the enzyme glyceraldehyde 3phosphate dehydrogenase in an attractive way, and the compounds tiliroside, chalepin and 3', 4', 5',5,7-pentamethoxyflavone were those that obtained Lower interaction energy, showing to be more stable in complexes with the active site of the enzyme (GADPH).In Figure 2 it can be seen that all the compounds have approached, through their ring systems, the amino acids HIS 194 and CYS 166, which are essential for catalytic activity of the enzyme, since this activity involves the nucleophilic attack of catalytic cystine (CYS 166) on the substrate.This result suggests that all ring structures of the compounds, besides the polar groups, are extremely important for the pharmacological activity of these compounds.

Conclusions:
The computational study carried out in this work allowed a better view, at a molecular level, regarding the interaction of compounds 1-6 with the enzyme, showing that the compounds that have lower IC 50 also have more stable energy of drug-receptor binding.This result suggests that there is a more selective mechanism of interaction in GAPDH.
studies have shown excellent results for inhibition of the GAPDH enzyme by aromatic compounds, such as the tiliroside flavonoids , and chalepin, which is a synthetic coumarin derivative [10] (Figure 1).

Figure 1 . 2 . 1
Figure 1.Glyceraldehyde 3-phosphate dehydrogenase inhibitors involved in the study crystallographic structure of the enzymatic target GAPDH was obtained from the Protein Data Bank database [PDB ID: 1K3T].AutoDock 4.0 software [26] was used as the choice to conduct the studies in the GAPDH target.The AutoDock Tools module was used to prepare and analyze the computational simulations.The AutoGrid 4.0 software was used to generate the maps for the binders.The box was positioned in the catalytic region of the enzyme.The Lamarckian Genetic algorithm (GA-LS) was chosen to search for the best conformations [27-29].100 runs were performed for each binder (genetic algorithm with local search).

Figure 2
Figure 2 shows the more stable conformation of compounds 1-6 at the site of action of the GADPH enzyme.

Table 1 .
It can be observed that relation to the octanol / water partition coefficient (LogP) calculated by ALOGPS 2.1, the values found for compounds 1-6 can be visualized in

Table 1 .
LogP and logS values of the

Table 2 .
Descriptors used in analysis

Table 3 .
Result of the docking study of the compounds with the enzyme glyceraldehyde 3-phosphate dehydrogenase.