Molecular modeling study of acrylamides derivatives as inhibitors of the NS3/NS2B serine proteases of the dengue virus

Abstract

Dengue fever is an acute viral infection caused by the mosquito of the Aedes genus, with the largest incidence in tropical and sub-tropical regions of the world. There are no specific treatments against the dengue virus, and only the symptoms resulting from the disease are treated. The NS3/NS2B serine protease enzyme is essential for the life cycle of the virus and a promising target for drug development against the virus. In this work, acrylamide derivatives obtained from the literature data were submitted to molecular modeling studies. According to the results of the molecular docking calculations and subsequent consensual analysis, which consists of a statistical treatment used to assign the same importance to the results from different programs, and visual inspection we selected three compounds, which make hydrogen bonds with the amino acid residues His51, Asp75, Ser135, Gly151 and Gly153. Thus, Molecular Dynamics simulations were performed with three selected ligands using the hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) method, which the semiempirical AM1 Hamiltonian was used to describe the QM part and the OPLS-AA force field as method of Molecular Mechanics . The Root Mean Square Deviation (RMSD) graphs showed that systems were stabilized in 10 ns. Also, through the contribution of individual residues we observed that key residues, such as Ser34, Trp50, Lys73 and Gly151, were responsible for stabilization of the complex in the active site of the dengue enzyme.