Prospecção de inibidores da formação do dímero da NS1 de três principais Flavivirus de importância médica: uma abordagem por dinâmica molecular e triagem virtual de compostos

Abstract

Diseases caused by viruses of the Flavivirus genus are among the main diseases that affect the world, especially Brazil, and they are a serious public health problem. In Brazil, three of them stand out: dengue, yellow fever and Zika. The non-structural protein 1 (NS1), encoded by this viral genus, in its dimeric form plays important roles in the pathogenesis and RNA replication of these viruses. However, there is no available pharmacological treatment with antiviral action. Therefore, the identification of chemicals with the potential to inhibit the formation of the NS1 protein dimer of DENV, YFV and ZIKV would enable them to act as a multi-target drug. For this, with the aid of TM-Align we selected conformations of the NS1 protein monomer with similar ß-roll domain structure (TM-Score ≥ 0.57) among the three virus species from conformations obtained from molecular dynamics simulations performed in GROMACS in 5 replicates of 150 ns for each species. This analysis resulted in the selection of two NS1 conformations for each viral species, totaling six NS1 conformations. After selecting the protein structures, a virtual screening of compounds from the natural products catalog of the ZINC database with the six NS1 structures was performed using AutoDock Vina. From the result of anchoring for each NS1 protein, the 100 best compounds were classified according to two criteria: affinity and efficiency. In the affinity classification, the ranked compounds for each NS1 conformation were compared and five of them were found in common with the NS1 of the three viral species. Of these, four were at toxicological risk under the OSIRIS Property Explorer program. After removing the toxic fragment, a new anchor showed a reduction in the affinity of the molecule for NS1, but still with promising energy scores (between -7.5 kcal/mol and -9.6 kcal/mol). Among the compounds classified by efficiency criteria, only two were observed in common to the species, one of which had toxicological risk and did not fit in parameters of compounds with pharmacological potential after removal of the toxic fragment. The results obtained here demonstrate the high similarity of NS1 proteins in the Flavivirus genus and affinity for the same compounds; thus justifying the potential of these six macromolecules in multitarget therapy. The theoretical-computational data presented support future in vitro and in vivo experiments, such as tests to assess the replicative capacity of the virus in the presence of highlighted bioactive molecules. Therefore, the information presented in this work will be relevant for the development of a molecule with the potential to inhibit the formation of the NS1 protein dimer.