3.2  Sialic acids as molecular targets of CLQ and CLQ-OH
Neu5Ac is the predominant sialic acid found in human glycoproteins and gangliosides. When CLQ was merged with Neu5Ac, a quasi-instantaneous fit occurred between the two molecules, whose global shapes in water are geometrically complementary Fig. 2 (a). This is particularly obvious in the views of the CLQ–Neu5Ac complex in mixed surface/balls and sticks rendition Fig. 2(a,b). The interaction was driven by the positioning of the negative charge of the carboxylate group of Neu5Ac and one of the two cationic charges of CLQ (pKa 10.2) Fig. 2(c). The energy of interaction of this complex was estimated to be -47 kJ.mol−1. As coronaviruses preferentially interact with 9-O-acetyl-N-acetylneuraminic acid (9-O-SIA) [10], this study used a similar molecular modelling approach to assess whether CLQ could also interact with this specific sialic acid. A good fit between CLQ and 9-O-SIA was obtained Fig. 2(d–f), with an energy of interaction of -45 kJ.mol−1. In this case, the carboxylate group of the sialic acid interacted with the cationic group of the nitrogen-containing ring of CLQ (pKa 8.1) Fig. 2(d). The complex was further stabilized by OH-π and van der Waals interactions.
Fig. 2 Molecular modelling of chloroquine (CLQ) interaction with sialic acids. (a,b) Surface representation of the CLQ–sialic acid (Neu5Ac) complex. Two opposite views of the complex are shown. Note the geometric complementarity between the L-shape conformer of CLQ dissolved in water (in blue) and Neu5Ac (in red). (c) Neu5Ac bound to CLQ via a combination of CH-π and electrostatic interactions with one of the cationic groups of CLQ (+). (d) Molecular modelling of CLQ bound to N-acetyl-9-O-acetylneuraminic acid (9-O-SIA). From right to left, the dashed lines indicate a series of van der Waals, OH-π and electrostatic contacts with both cationic groups of CLQ (+). (e,f) Surface representations of the CLQ–9-O-SIA complex.
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.