Next, CLQ-OH was tested to assess whether it could, as CLQ, bind to 9-O-SIA (Fig. 3 ). The complex obtained with CLQ-OH was very similar to that obtained with CLQ [compare Fig. 3(a,b) with Fig. 2(e,f), although several conformational adjustments occurred during the simulations. Interestingly, the OH group of CLQ-OH reinforced the binding of CLQ to sialic acid through establishment of a hydrogen bond Fig. 3(c,d). Overall, this hydrogen bond compensated for the slight loss of energy caused by the conformational rearrangement, and the energy of interaction of the complex was estimated to be -46 kJ.mol−1, which is very close to the value obtained for CLQ (-45 kJ.mol−1).
Fig. 3 Molecular modelling of hydroxychloroquine (CLQ-OH) interaction with sialic acids. (a,b) Surface representation of CLQ-OH bound to N-acetyl-9-O-acetylneuraminic acid (9-O-SIA). Two opposite views of the complex are shown. Note the geometric complementarity between CLQ-OH (in blue) and 9-O-SIA (in red). (c,d) Molecular mechanism of CLQ-OH binding to 9-O-SIA: combination of electrostatic interactions and hydrogen bonding.