Prediction of Single Point Mutations in Ganglioside-Binding Domain of SARS-CoV-2 S and Their Effects on Binding of 9-O-Acetylated Sialic Acid and Hidroxychloroquine

Abstract

The infectious disease CoViD-19 is caused by a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also referred to as hCoV-19. A possible infection mechanism includes dual host receptor recognitions by the SARS-CoV-2 transmembrane spike (S) glycoproteins. SARS-CoV-2 S contains two different domains, the receptor-binding domain (RBD) and the N-terminal domain (NTD), which interact with the angiotensin-converting enzyme 2 (ACE2) and the ganglioside-rich domain of the plasma membrane at the surface of respiratory cell, respectively. The NTD amino acid residues (111-162) form a functional ganglioside-binding domain (GBD) that is conserved in all clinical isolates. Herein, the single point mutations (SPMs) of the GBD residues to which the virus is prone during genetic adaptation are predicted using an in silico protein engineering approach. Consequently, their effects on the attachment of SARS-CoV-2 S to the ganglioside-linked 9-O-acetylated sialic acid (9-O-Ac-Sia) are explored using molecular docking simulations. Val120Tyr and Asn122Trp are found to be the most likely SPMs in the GBD of SARS-CoV-2 S being involved in very specific recognition with 9-O-Ac-Sia through electrostatic interactions. Val120Tyr and Asn122Trp are also found to be the most likely SPMs in the GBD of SARS-CoV-2 S that is involved in conspicuously hydrophobic recognition with hidroxychloroquine (Hcq), thereby indicating the ability of Hcq to competitively inhibit GBD interactions with lipid rafts. However, the considerably non-specific binding of Hcq and the micromolar range of the dissociation constants of the SARS-CoV-2 S/Hcq complexes do not support the proposal of treating Hcq as a drug candidate. Maintaining a clear resemblance of the structure of a potential drug candidate to a natural substrate, accompanied by essential functional group modifications, may be a usable guideline for the structure-based design of anti-CoViD-19 drugs.<br>

Predicted single point mutations in ganglioside-binding domain of SARS-CoV-2 S and recognition by 9-O-acetylated sialic acid and hydroxychloroquine

“…3) is characterized hereafter, considering that a similar, preliminary discussion on the Asn122Trp/9-O-Ac-Sia interaction mode is available online. 37 Val120Tyr increases the hydrophobic nature of the GBD/9-O-Ac-Sia interaction. Val159 from the P3 (Phe133, Val159 and Tyr160) hydrophobic pocket accommodates the 5-N-Ac methyl, while Phe135 from the P4 (Phe135 and Cys136) hydrophobic pocket accommodates the 2-O methyl (Fig.…”