Computational insights into anti-Zika quinazoline compounds: Density functional theory analysis, spectral properties, and molecular dynamics simulations

Zika disease, caused by the Zika virus (ZIKV), a mosquito-borne flavivirus, is a leading factor in the emergence and reemergence of serious illnesses. The compounds N-[4-((3-bromo-4-fluorophenyl)amino]-7-methoxyquinazolin-6-yl)-2-butynamide (1), N-[4-((4'-6-difluoro-[1,1'-biphenyl]-3-yl)amino)quinazolin-6-yl]-2-butynamide (2), and N-[4-((3-fluorophenyl) amino)-7-methoxyquinazolin-6-yl]but-2-ynamide (3) have been reported to exhibit anti-ZIKV activity. In this study, we performed geometry optimizations and structural analysis of these compounds using the B3LYP/6-31G** method. On the basis of the optimized geometries, the electronic properties, infrared (IR) assignments, and thermodynamic parameters were evaluated. The results indicate that these molecules maintain robust conformations in their core rings, with notable variations in the conformations of their side chains and functional groups. It was also observed that the rotational temperatures increase as the rotational constants decrease. The evaluated small HOMO-LUMO energy gaps and molecular electrostatic potential maps suggest high chemical reactivity, indicating ease of intramolecular charge transfer within the molecules. Infrared assignments for normal mode vibrations in the range of 400 to 3800 cm-1 were carried out successfully and compared for all three compounds. In addition, to study the structure function, the docking of these molecules along with the control molecule afatinib was performed with the methyltransferase enzyme of the Zika virus. The top-ranked docked complexes were subjected to a molecular dynamics simulation run of 200 ns duration. These theoretical calculations help us to understand how these compounds can interact with enzymes that are involved in the metabolic pathways of the Zika virus.