RESUMO
Aflatoxins are secondary metabolites of the fungi Aspergillus flavus and A. parasiticus. Among them, aflatoxin B1 (AFB1) is the most frequent type in nature and the most carcinogenic for mammals. It can contaminate many kinds of food like seeds, oil, olives, milk, dairy products, corn and meat, causing acute and chronic damages to the organism, especially in the liver, being, for this reason, considered highly hepatotoxic. AFB1 is also a mixed inhibitor of the enzyme acetylcholinesterase (AChE). This fact, together with its high toxicity and carcinogenicity, turns AFB1 into a potential chemical and biological warfare agent, as well as its metabolites. In order to investigate this, we performed inedited molecular modeling studies on the interactions of AFB1 and its metabolites inside the peripheral anionic site of human AChE (HssAChE), to verify their stability, suggest the preferential ways of inhibition, and compare their behavior to each other. Our results suggest that all metabolites can be better inhibitors of HssAChE than AFB1 and that AFBO and AFM1, the most toxic and carcinogenic metabolites of AFB1, are also the most effective HssAChE inhibitors among the AFB1 metabolites. Communicated by Ramaswamy H. Sarma.
Assuntos
Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Aflatoxina B1/química , Aflatoxina B1/metabolismo , Metaboloma , Modelos Moleculares , Ânions , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , TermodinâmicaRESUMO
Malaria is a disease caused by protozoan parasites of the genus Plasmodium that affects millions of people worldwide. In recent years there have been parasite resistances to several drugs, including the first-line antimalarial treatment. With the aim of proposing new drugs candidates for the treatment of disease, Quantitative Structureâ»Activity Relationship (QSAR) methodology was applied to 83 N-myristoyltransferase inhibitors, synthesized by Leatherbarrow et al. The QSAR models were developed using 63 compounds, the training set, and externally validated using 20 compounds, the test set. Ten different alignments for the two test sets were tested and the models were generated by the technique that combines genetic algorithms and partial least squares. The best model shows r² = 0.757, q²adjusted = 0.634, R²pred = 0.746, R²m = 0.716, ∆R²m = 0.133, R²p = 0.609, and R²r = 0.110. This work suggested a good correlation with the experimental results and allows the design of new potent N-myristoyltransferase inhibitors.
Assuntos
Aciltransferases/antagonistas & inibidores , Antimaláricos/química , Antimaláricos/farmacologia , Algoritmos , Desenho de Fármacos , Resistência a Medicamentos/efeitos dos fármacos , Humanos , Análise dos Mínimos Quadrados , Modelos Moleculares , Plasmodium/efeitos dos fármacos , Plasmodium/enzimologia , Proteínas de Protozoários/antagonistas & inibidores , Relação Quantitativa Estrutura-AtividadeRESUMO
The most common type of aflatoxin (AFT) found in nature is aflatoxin B1 (AFB1). This micotoxin is extremely hepatotoxic and carcinogenic to mammals, with acute and chronic effects. It is believed that this could be related to the capacity of AFB1 and its metabolites in inhibiting the enzyme acetylcholinesterase (AChE). In a previous work, we performed an inedited theoretical investigation on the binding modes of these molecules on the peripheral anionic site (PAS) of human AChE (HssAChE), revealing that the metabolites can also bind in the PAS in the same way as AFB1. Here, we investigated the binding modes of these compounds on the catalytic anionic site (CAS) of HssAChE to compare the affinity of the metabolites for both binding sites as well as verify which is the preferential one. Our results corroborated with experimental studies pointing to AFB1 and its metabolites as mixed-type inhibitors, and pointed to the residues relevant for the stabilization of these compounds on the CAS of HssAChE.
Assuntos
Acetilcolinesterase/metabolismo , Aflatoxina B1/metabolismo , Inibidores da Colinesterase/metabolismo , Modelos Moleculares , Acetilcolinesterase/química , Aflatoxina B1/química , Domínio Catalítico , Inibidores da Colinesterase/química , Humanos , Interações Hidrofóbicas e HidrofílicasRESUMO
The rise of the mosquitoes-transmitted diseases, like dengue, zika and chikungunya in Brazil in the last years has increased concerns on protection against mosquitoes bites. However, the prohibitive prices of the commercially available repellents for the majority of the Brazilian population has provoked a search for cheaper solutions, like the use of the homemade ethanolic extract of Indian clove (Syzygium aromaticum L.) as repellent, which has been reported as quite efficient by the local press. In order to verify this, we performed here the quantification of the main components of this extract through high-performance thin-layer chromatography (HPTLC)-densitometry and evaluated its efficiency as a repellent and its acetylcholinesterase (AChE) inhibition capacity. Our results have proved HPTLC-densitometry as an efficient and appropriate method for this quantification and confirmed the repellency activity, as well as its capacity of AChE inhibition.