Integrating Computational Approaches from Non-synonymous Sequence Variations to Molecular Structure for Drug Repositioning Targeting the SARS-CoV-2 Spike Protein

In this chapter, we demonstrate how bioinformatics and molecular modeling can be used to study the effects of non-synonymous variations (NSVs) in a protein sequence of interest. Here we investigate the impact of NSVs in the alpha (α), beta (β), delta (δ), gamma (γ), and omicron (o) variants of concern (VOC) that are present in the receptor-binding domain (RBD) contained in the spike-host interface. By integrating techniques such as biological database manipulation, multiple sequence alignments, structural analysis, and virtual screening, we examine the impact of NSVs on the three-dimensional structure of spike and their interactions with potential drug repositioning candidates. The influence exerted by NSVs on this interface of interaction between the compounds and critical amino acids in the binding domain resulted in different impacts on the protein structure and, consequently, on the top-ranked drugs. This comprehensive approach enables us to gain insights into the relationship between NSVs and the biological sequence at the molecular and structural level, as well as their respective interactions with potential drug repositioning candidates.