Manoelito Coelho dos Santos Junior

8-Methoxypsoralen is a competitive inhibitor of glutathione S-transferase P1-1

The blood-brain barrier (BBB) is known to protect healthy brain cells from potentially dangerous chemical agents, but there are many evidences supporting the idea that this protective action is extended to tumor cells. Since the process of angiogenesis in brain tumors leads to BBB breakdown, biochemical characteristics of the BBB seem to be more relevant than physical barriers to protect tumor cells from chemotherapy. In fact, a number of resistance related factors were already demonstrated to be component of both BBB and tumor cells. The enzyme glutathione S-transferases (GST) detoxify electrophilic xenobiotics and endogenous secondary metabolites formed during oxidative stress. A role has been attributed to GST in the resistance of cancer cells to chemotherapeutic agents. This study characterized 8-methoxypsoralen (8-MOP) as a human GST P1-1 (hGST P1-1) inhibitor. To identify and characterize the potential inhibitory activity of 8-MOP, we studied the enzyme kinetics of the conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) with GSH catalyzed by hGST P1-1. We report here that 8-MOP competitively inhibited hGST P1-1 relative to CDNB, but there was an uncompetitive inhibition relative to GSH. Chromatographic analyses suggest that 8-MOP is not a substrate. Molecular docking simulations suggest that 8-MOP binds to the active site, but its position prevents the GSH conjugation. Thus, we conclude that 8-MOP is a promising prototype for new GST inhibitors pharmacologically useful in the treatment of neurodegenerative disorders and the resistance of cancer to chemotherapy.

Structure-based drug design studies of UDP-N-acetylglucosamine pyrophosphosrylase, a key enzyme for the control of witches’ broom disease

BackgroundThe witches’ broom disease is a plague caused by Moniliophthora perniciosa in the Theobroma cacao, which has been reducing the cocoa production since 1989. This issue motivated a genome project that has showing several new molecular targets, which can be developed inhibitors in order to control the plague. Among the molecular targets obtained, the UDP-N-acetylglucosamine pyrophosphorylase (UNAcP) is a key enzyme to construct the fungal cell wall. The inhibition of this enzyme results in the fungal cell death.ResultsThe results show that the molecular recognition of the enzyme with the substrates occurs mainly by hydrogen bonds between ligands and Arg116, Arg383, Gly381, and Lys408 amino acids; and few hydrophobic interactions with Tyr382 and Lys123 residues.ConclusionsAmong the compounds analyzed, the NAG5 showed the best binding energy (−95.2 kcal/mol). The next steps for the control of witches’ broom plague involve the synthesis and biological evaluation of these compounds, which are in progress.

Identification of Lutzomyia longipalpis Odorant Binding Protein Modulators by Comparative Modeling, Hierarchical Virtual Screening, and Molecular Dynamics

Visceral leishmaniasis (VL) is the second most important vector-borne disease in the world. It is transmitted by Lutzomyia longipalpis in America; therefore, controlling the vector is essential to prevent the disease, especially using traps with chemical attractants. It is known that odorant binding proteins (OBPs) act at the first odor selection level, so in silico methodology was used to identify putative vector chemical modulators based on OBPs on known ligand structures. Therefore, 3D structures of L. longipalpis OBP were predicted through different comparative modeling methods. The best model was subjected to molecular dynamics studies. Then, a hierarchical virtual screening approach filtered OBP modulator-like compounds from ZINC12 biogenic database based in global chemical space, using principal components from ChemGPS-NP server. Such compounds then were evaluated and ranked according to their affinity with the OBP orthosteric site by molecular docking in DOCK 6.7. The compounds were scored by Grid Score function and top five ranked poses had their intermolecular complex interactions analyzed in PLIP server. Most ligands in the top of the rank were lysophospholipids, which could potentially interact with the OBP hydrophobic pocket through Phe72, Tyr76, Ile79, Ala87, Lys88, Asp92, Phe61, Leu75, Trp113, His120, and Phe122 residues and H-bonding with His120 and Phe122. Next, compounds in the top of the rank were evaluated by 50 ns MD and the results showed that the phosphate group of these compounds could set a salt bridge with His110. Additionally, Tyr76, Ala87, Met91, Trp113, and Phe122 were important to hydrophobic interactions with the ligand. These results highlight the importance of accurate assessments such as MD studies in order to analyze the docking results in the identification of new odorant modulators.