Design, synthesis, molecular modelling, and in vitro evaluation of tricyclic coumarins against Trypanosoma cruzi.

Chagas disease is caused by infection with the parasite protozoan Trypanosoma cruzi and affects about 8 million people in 21 countries in Latin America. The main form of treatment of this disease is still based on the use of two drugs, benznidazole and nifurtimox, which both present low cure rates in the chronic phase and often have serious side-effects. Herein, we describe the synthesis of tricyclic coumarins that were obtained via NHC organocatalysis and evaluation of their trypanocidal activity. Molecular docking studies against trypanosomal enzyme triosephosphate isomerase (TIM) were carried out, as well as a theoretical study of the physicochemical parameters. The tricyclic coumarins were tested in vitro against the intracellular forms of Trypanosoma cruzi. Among the 18 compounds tested, 10 were more active than the reference drug benznidazole. The trypanocidal activity of the lead compound was rationalized by molecular docking study which suggested the strong interaction with the enzyme TIM by T. cruzi and therefore indicating a possible mode of action. Furthermore, the selectivity index of eight tricyclic coumarins with high anti-T. cruzi activity was above 50 and thus showing that these lead compounds are viable candidates for further in vivo assays.

Asymmetric biodegradation of the nerve agents Sarin and VX by human dUTPase: chemometrics, molecular docking and hybrid QM/MM calculations.

Organophosphorus compounds (OP) nerve agents are among the most toxic chemical substances known. Their toxicity is due to their ability to bind to acetylcholinesterase. Currently, some enzymes, such as phosphotriesterase, human serum paraoxonase 1 and diisopropyl fluorophosphatase, capable of degrading OP, have been characterized. Regarding the importance of bioremediation methods for detoxication of OP, this work aims to study the interaction modes between the human human deoxyuridine triphosphate nucleotidohydrolase (dUTPase) and Sarin and VX, considering their Rp and Sp enantiomers, to evaluate the asymmetric catalysis of those compounds. In previous work, this enzyme has shown good potential to degrade phosphotriesters, and based on this characteristic, we have applied the human dUTPase to the OP degradation. Molecular docking, chemometrics and mixed quantum and molecular mechanics calculations have been employed, showing a good interaction between dUTPase and OP. Two possible reaction mechanisms were tested, and according to our theoretical results, the catalytic degradation of OP by dUTPase can take place via both mechanisms, beyond being stereoselective, that is, dUTPase cleaves one enantiomer preferentially in relation to other. Chemometric techniques provided excellent assistance for performing this theoretical investigation. The dUTPase study shows importance by the fact of it being a human enzyme. Communicated by Ramaswamy H. Sarma.

Reactivation steps by 2-PAM of tabun-inhibited human acetylcholinesterase: reducing the computational cost in hybrid QM/MM methods.

The present work describes a simple integrated Quantum Mechanics/Molecular Mechanics method developed to study the reactivation steps by pralidoxime (2-PAM) of acetylcholinesterase (AChE) inhibited by the neurotoxic agent Tabun. The method was tested on an AChE model and showed to be able to corroborate most of the results obtained before, through a more complex and time-consuming methodology, proving to be suitable to this kind of mechanistic study at a lower computational cost.

Construction and assessment of reaction models of Class I EPSP synthase. Part II: investigation of the EPSP ketal.

Although the proposed mechanisms are reasonable, there are still many questions about the 5-enolpyruvyl shikimate-3-phosphate (EPSP) synthase mechanism that are difficult to answer by experimental means alone. EPSP synthase is a key enzyme in the shikimic acid pathway, which is found only in plants and some micro-organisms and is also molecular target of glyphosate, active component of one of the top-selling herbicides. In the study of reaction mechanism of EPSP synthase, in addition to inorganic phosphate and EPSP products, after long time at equilibrium, it was shown that a side product is formed, the EPSP ketal. In this line, studies using density functional theory (DFT) techniques were performed to investigate the reaction mechanism of formation of EPSP and the corresponding ketal. Our findings indicate some key amino acid residues in the EPSP synthase mechanism and a possible route for the formation of the EPSP ketal.