Journal
MOLECULES
Volume 28, Issue 17, Pages -Publisher
MDPI
DOI: 10.3390/molecules28176413
Keywords
cryptic binding sites; glycosaminoglycans; molecular docking; molecular dynamics; binding free energy; SARS-CoV-2 spike glycoprotein
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This study conducted a computational analysis on the binding of four oligosaccharide building blocks from novel marine sulfated glycans to the receptor-binding domain of SARS-CoV-2. It identified two binding sites and revealed the key structural features and interactions driving ligand binding. This study provided important structural information for the development of these novel glycans as potential therapeutics.
The entry of SARS-CoV-2 into the host cell is mediated by its S-glycoprotein (SGP). Sulfated glycans bind to the SGP receptor-binding domain (RBD), which forms a ternary complex with its receptor angiotensin converting enzyme 2. Here, we have conducted a thorough and systematic computational study of the binding of four oligosaccharide building blocks from novel marine sulfated glycans (isolated from Pentacta pygmaea and Isostichopus badionotus) to the non-glycosylated and glycosylated RBD. Blind docking studies using three docking programs identified five potential cryptic binding sites. Extensive site-targeted docking and molecular dynamics simulations using two force fields confirmed only two binding sites (Sites 1 and 5) for these novel, highly charged sulfated glycans, which were also confirmed by previously published reports. This work showed the structural features and key interactions driving ligand binding. A previous study predicted Site 2 to be a potential binding site, which was not observed here. The use of several molecular modeling approaches gave a comprehensive assessment. The detailed comparative study utilizing multiple modeling approaches is the first of its kind for novel glycan-SGP interaction characterization. This study provided insights into the key structural features of these novel glycans as they are considered for development as potential therapeutics.
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