Abstract
Conventional drug development strategies typically use pocket in protein structures as drug-target sites. They overlook the plausible effects of protein evolvability and resistant mutations on protein structure which in turn may impair protein-drug interaction. In this study, we used an integrated evolution and structure guided strategy to develop potential evolutionary-escape resistant therapeutics using receptor binding domain (RBD) of SARS-CoV-2 spike-protein/S-protein as a model. Deploying an ensemble of sequence space exploratory tools including co-evolutionary analysis and deep mutational scans we provide a quantitative insight into the evolutionarily constrained subspace of the RBD sequence-space. Guided by molecular simulation and structure network analysis we highlight regions inside the RBD, which are critical for providing structural integrity and conformational flexibility. Using fuzzy C-means clustering we combined evolutionary and structural features of RBD and identified a critical region. Subsequently, we used computational drug screening using a library of 1615 small molecules and identified one lead molecule, which is expected to target the identified region, critical for evolvability and structural stability of RBD. This integrated evolution-structure guided strategy to develop evolutionary-escape resistant lead molecules have potential general applications beyond SARS-CoV-2.
Keywords: Co-evolution; Covid-19; Deep mutation scan; Druggability; Fuzzy C-means clustering; Machine learning; Molecular dynamic simulation; Receptor binding domain; SARS-CoV-2; Sequence space analysis; Structure network analysis.
【저자키워드】 COVID-19, SARS-CoV-2, machine learning, druggability, molecular dynamic simulation, Receptor binding domain, co-evolution, Structure network analysis., Sequence space analysis, Fuzzy C-means clustering, Deep mutation scan, 【초록키워드】 Structure, Evolution, Mutation, Protein, Region, stability, RBD, Clustering, network analysis, small molecule, exploratory, Quantitative, Critical, binding, Molecular simulation, Interaction, drug-target, Analysis, sequence, machine, Computational drug, conformational flexibility, Effect, feature, deep, highlight, develop, the RBD, expected, turn, impair, Conventional, 【제목키워드】 RBD, feature, the SARS-CoV-2,