Utilização do QSAR-3D no planejamento racional de novos inibidores HDAC8 do Schistosoma mansoni

Abstract

For some time, health agencies worldwide have shown great concern about the prevalence of schistosomiasis, as well as resistance to current therapies. Schistosomiasis is a disease included in the group of neglected tropical diseases and is caused by the worm S. mansoni. For the development of new compounds which aim to combat this parasite, it is of great interest to study the inhibition of essential targets in its cycle. Among the various targets studied, the histone deacetylase 8 enzyme from S. mansoni (smHDAC8) is an attractive protein for planning schistosomicidal drugs, justifying the fact that smHDAC8 is essential for the parasite. Hydroxinamic acid derivatives are potent enzyme inhibitors of smHDAC8. Thus, aiming at the rational planning of new smHDAC8 inhibitors, a QSAR study was carried out to produce a model capable of predicting the biological activity for this class of compounds. All structures were designed and optimized for the docking stage. The conformations obtained in the docking were used to calculate the descriptors and, consequently, construction of the QSAR-3D model. A model with 3 Lennard-Jones and 1 Coulomb descriptor was able to predict the biological activity for the training set (R2 = 0.92, RMSEC = 0.42). In addition, it was able to predict the IC50 value for an external subset (Q2ext = 0.85) of samples. The interpretation of the descriptors led to several insights on the relationship between activity and structure of hydroxamate-based smHDAC8 inhibitors. In this way, new compounds can be planned and have their biological activities predicted in silico by the QSAR-3D model.