3.1  Structural and conformational analysis of CLQ and CLQ-OH in water
The chemical structures of CLQ and CLQ-OH are shown in Fig. 1 (a,b). The only difference between the two molecules is the presence of a terminal hydroxyl group in CLQ-OH. This OH group has a marked influence on the conformation and water-solubilization properties of the drug. CLQ-OH may adopt a wide range of conformations, the most stable being the extended one shown in Fig. 1(c). When immersed in a periodic box of 31.5 Å2 with 1042 water molecules, the system reached, at equilibrium, an estimated energy of interaction of -92 kJ.mol−1, accounting for 56 water molecules solvating CLQ-OH Fig. 1(d). In contrast, due to an intramolecular hydrophobic effect, CLQ appeared to be more condensed than CLQ-OH Fig. 1(e). At equilibrium, CLQ was surrounded by 58 water molecules with an energy of interaction of -79 kJ.mol−1 Fig. 1(f).
Fig. 1 Chemical structure of chloroquine (CLQ) and hydroxychloroquine (CLQ-OH). (a) CLQ. (b) CLQ-OH. (c) CLQ-OH extended conformer. (d) CLQ-OH in water. (e) Typical condensed conformer of CLQ. (f) CLQ in water. The molecules in (c–f) are shown in either tube or sphere rendering (carbon, green; nitrogen, blue; oxygen, red; hydrogen, white). In (c) and (e), the chlorine atom of CLQ and CLQ-OH is indicated by an arrow.
These water-compatible conformations of CLQ and CLQ-OH were used as initial conditions for studying the interaction of these drugs with sialic acids and gangliosides.