Comparative molecular dynamics simulations of n-octyl-beta-D-galactopyranoside (beta-C8Gal) and n-octyl-beta-D-glucopyranoside (beta-C8Glc) micelles in aqueous solution have been performed to explore the influence of carbohydrate stereochemistry on glycolipid properties at the atomic level. In particular, we explore the hypothesis that differences in T(m) and T(c) for beta-C8Gal and beta-C8Glc in lyotropic systems arise from a more extensive hydrogen bonding network between beta-C8Gal headgroups relative to beta-C8Glc, due to the axial 4-OH group in beta-C8Gal. Good agreement of the 13 ns micelle-water simulations with available experimental information is found. The micelles exhibit a similar shape, size, and degree of exposed alkyl chain surface area. We find net inter- and intra-headgroup hydrogen bonding is also similar for beta-C8Gal and beta-C8Glc, although n-octyl-beta-D-galactopyranoside micelles do exhibit a slightly greater degree of inter- and intra-headgroup hydrogen bonding. However, the main distinction in the calculated microscopic behavior of beta-C8Glc and beta-C8Gal micelles lies in solvent interactions, where beta-d-glucosyl headgroups are considerably more solvated (mainly at the equatorial O4 oxygen). These results agree with preceding theoretical and experimental studies of monosaccharides in aqueous solution. A number of long water residence times are found for solvent surrounding both micelle types, the largest of which are associated with surface protrusions involving headgroup clusters. Our simulations, therefore, predict differences in hydrogen bonding for the two headgroup stereochemistries, including a small difference in inter-headgroup interactions, which may contribute to the higher T(m) and T(c) values of beta-C8Gal surfactants relative to beta-C8Glc in lyotropic systems.
Zika virus (ZIKV) represents a re-emerging threat to global health due to its association with congenital birth defects. ZIKV NS2B-NS3 protease is crucial for virus replication by cleaving viral polyprotein at various junctions to release viral proteins and cause cytotoxic effects in ZIKV-infected cells. This study characterized the inhibitory effects of doxycycline against ZIKV NS2B-NS3 protease and viral replication in human skin cells. The in silico data showed that doxycycline binds to the active site of ZIKV protease at a low docking energy (-7.8 Kcal/mol) via four hydrogen bonds with the protease residues TYR1130, SER1135, GLY1151, and ASP83. Doxycycline efficiently inhibited viral NS2B-NS3 protease at average human temperature (37 °C) and human temperature with a high fever during virus infection (40 °C). Interestingly, doxycycline showed a higher inhibitory effect at 40 °C (IC50 = 5.3 µM) compared to 37 °C (9.9 µM). The virus replication was considerably reduced by increasing the concentration of doxycycline. An approximately 50% reduction in virus replication was observed at 20 µM of doxycycline. Treatment with 20 µM of doxycycline reduced the cytopathic effects (CPE), and the 40 µM of doxycycline almost eliminated the CPE of human skin cells. This study showed that doxycycline binds to the ZIKV protease and inhibits its catalytic activity at a low micro-molecular concentration range. Treatment of human skin fibroblast with doxycycline eliminated ZIKV infection and protected the cells against the cytopathic effects of the infection.