An important stage in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) life cycle is the binding of the spike (S) protein to the angiotensin converting enzyme-2 (ACE2) host cell receptor. Therefore, to explore conserved features in spike protein dynamics and to identify potentially novel regions for drugging, we measured spike protein variability derived from 791 viral genomes and studied its properties by molecular dynamics (MD) simulation. The findings indicated that S2 subunit (heptad-repeat 1 (HR1), central helix (CH), and connector domain (CD) domains) showed low variability, low fluctuations in MD, and displayed a trimer cavity. By contrast, the receptor binding domain (RBD) domain, which is typically targeted in drug discovery programs, exhibits more sequence variability and flexibility. Interpretations from MD simulations suggest that the monomer form of spike protein is in constant motion showing transitions between an “up” and “down” state. In addition, the trimer cavity may function as a “bouncing spring” that may facilitate the homotrimer spike protein interactions with the ACE2 receptor. The feasibility of the trimer cavity as a potential drug target was examined by structure based virtual screening. Several hits were identified that have already been validated or suggested to inhibit the SARS-CoV-2 virus in published cell models. In particular, the data suggest an action mechanism for molecules including Chitosan and macrolides such as the mTOR (mammalian target of Rapamycin) pathway inhibitor Rapamycin. These findings identify a novel small molecule binding-site formed by the spike protein oligomer, that might assist in future drug discovery programs aimed at targeting the coronavirus (CoV) family of viruses.
【저자키워드】 SARS-CoV-2, spike glycoprotein, molecular docking, molecular dynamics, inhibitors, binding site, Coronavirus disease 2019 (COVID-19), Variability, trimer cavity, 【초록키워드】 viruses, ACE2, coronavirus, Drug discovery, feasibility, ACE2 receptor, Virtual screening, MD simulation, Spike protein, Receptor binding domain, Angiotensin converting enzyme-2, Protein, Region, RBD, pathway, drug target, CoV, molecular, inhibitor, mechanism, S2 subunit, binding, chitosan, Interaction, viral genome, acute respiratory syndrome, domains, domain, trimer, host cell receptor, monomer, sequence variability, mammalian, feature, Cell, fluctuation, identify, examined, conserved, indicated, addition, inhibit, facilitate, the spike protein, suggested, exhibit, assist, homotrimer, the SARS-CoV-2 virus, 【제목키워드】 spike, Cavity, novel, Site, the SARS-CoV-2,