Virtual screening e bioquímica quântica de potenciais inibidores da proteína não-estrutural 2 do vírus Chikungunya

Abstract

Chikungunya virus (CHIKV), belonging to the genus Alphavirus, is transmitted mainly by Aedes aegypti mosquitoes and is characterized by causing severe joint pain. Among the proteins that make up CHIKV, nsP2 has a central proteolytic activity in the maturation of the viral replication complex and, therefore, its inactivation eliminates virus replication. The aim of this work was to identify molecules with potential inhibitory activity of CHIKV targeting the proteolytic site of nsP2 (pdb: 3TRK). A virtual drug screening, consisting of the molecular docking (Vina software) of a compound library (obtained from the Zinc12 database) at the active site of the target protein was performed. Among 4999 compounds tested, 1690 presented a score that was more negative than -6.0 kcal / mol, indicating a higher probability of interaction. The two molecules with the best scores (ZINC67460397, denominated LIG1, and ZINC67513969, denominated LIG2) were selected for a more detailed analysis of the interaction with the protein through molecular dynamics. Thus, it was found that, even though they had the same score in the docking, the compounds presented very different behaviors in the interaction with nsP2. At the simulation time performed, only LIG1 stabilized at the nsP2 binding site. Important conformational adjustments were observed that led to this stabilization. The quantum study of the interactions of this ligand with the protein revealed strong attractive energies with the catalytic site residues (Cys1013 and His1083). The residues that showed the greatest contribution were Cys1013, Tyr1047, Asn1082, Met1238, Asn1011, Ala1046, Met1242, Ala1010, Ser1048, Tyr1079 and His1083. Residues with low energy input were also identified, which may guide the rational design of modifications to improve the interaction. The total binding energy calculated up to the 10 Å interaction radius was -89.5 kcal / mol. The observations made in this study provide a basis for the development of new drugs against the Chikungunya virus and point to LIG1 as a promising candidate. As a perspective, we intend to expand the screening analysis by evaluating a larger number of identified compounds.