Prediction of Single Point Mutations in Human Coronavirus and Their Effects on Binding to 9-O-Acetylated Sialic Acid and Hidroxychloroquine

Abstract

Due to the current spreading of the new disease CoViD-19, the World Health Organization formally declared a world pandemic on March 11, 2020. The present trends indicate that the pandemic will have an enormous clinical and economic impact on population health. Infections are initiated by the transmembrane spike (S) glycoproteins of human coronavirus (hCoV) binding to host receptors. Ongoing research and therapeutic product development are of vital importance for the successful treatment of CoViD-19. To contribute somewhat to the overall effort, herein, single point mutations (SPMs) of the binding site residues in hCoV-OC43 S that recognizes cellular surface components containing 9-O-acetylated sialic acid (9-O-Ac-Sia) are explored using an in silico protein engineering approach, while their effects on the binding of 9-O-Ac-Sia and Hidroxychloroquine (Hcq) are evaluated using molecular docking simulations. Thr31Met and Val84Arg are predicted to be the critical-most likely SPMs in hCoV-OC43 S for the binding of 9-O-Ac-Sia and Hcq, respectively, even though Thr31Met is a very likely SPM in the case of Hcq too. The corresponding modes of interaction indicate a comparable strength of the Thr31Met/9-O-Ac-Sia and Val84Arg/Hcq (or Thr31Met/Hcq) complexes. Given that the binding site is conserved in all CoV S glycoproteins that associate with 9-O-acetyl-sialoglycans, the high hydrophobic affinity of Hcq to hCoV-OC43 S speaks in favor of its ability to competitively inhibit rapid S-mediated virion attachment in high-density receptor environments, but its considerably low specificity to hCoV-OC43 S may be one of the key obstacles in considering the potential of Hcq to become a drug candidate.

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

“…26 This particular protocol was shown to be consistent for docking ligands in the crystal structures of viral proteins, [27][28][29][30][31] while the calculated binding free energies were well-correlated with the experimental inhibitory concentrations. 29 This approach predicted a dissociation constant of 48.7 µM for the hCoV-OC43 S/9-O-Ac-Sia complex, 14 a value that is in agreement with an experimental observation of 49.7 ± 10.7 µM. 25…”

“…E.g., the GBD of SARS-CoV-2 S binds 9-O-Ac-Sia (K d ≈ 17.5 µM) with about 3 times greater potency than does the interactive site of hCoV-OC43 S (K d ≈ 48.7 µM). 14,25 Each of the GBD residues is mutated to the other 24 (20 standard amino acids, phosphorylated Tyr, Ser and Thr, as well as hydroxyl Proline). All the single point mutants are energetically evaluated with reference to the original receptor (PDB ID: 6VSB).…”

“…Recent in vitro data 9 highlighted the observation that SARS-CoV-2 mutations, including several ones in the spike glycoprotein, 9,10 are not an infrequent event and that certain SARS-CoV-2 mutations confer a greater pathogenic effect than others. 9 In this article, the likely SPMs in the GBD of SARS-CoV-2 S are predicted using an in silico protein engineering approach [11][12][13][14] in a systematic fashion. Consequently, a question, how the most likely SPMs affect the affinity and specificity of 9-O-Ac-Sia and Hcq to the GBD of SARS-CoV-2 S, is explored.…”

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

“…Recent in vitro data 11 highlighted the observation that SARS-CoV-2 mutations, including several ones in the spike glycoprotein, 11,12 are not an infrequent event and that certain SARS-CoV-2 mutations confer a greater pathogenic effect than others. 11 In this study, likely SPMs in the GBD of SARS-CoV-2 S are predicted using an in silico protein engineering approach [13][14][15][16] in a systematic fashion. Consequently, a question, how the most likely SPMs affect the affinity and specificity of 9-O-Ac-Sia and Hcq to GBD, is explored.…”

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

“…Recent in vitro data 9 highlighted the observation that SARS-CoV-2 mutations, including several ones in the spike glycoprotein, 9,10 are not an infrequent event and that certain SARS-CoV-2 mutations confer a greater pathogenic effect than others. 9 In this article, the likely SPMs in the GBD of SARS-CoV-2 S are predicted using an in silico protein engineering approach [11][12][13][14] in a systematic fashion. Consequently, a question, how the most likely SPMs affect the affinity and specificity of 9-O-Ac-Sia and Hcq to the GBD of SARS-CoV-2 S, is explored.…”