Abstract
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.
Highlights
The global pandemic developing from December 2019 by a strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19) disease
Our current study focuses on understanding the variability of the trimer spike glycoprotein in SARS-CoV-2 with respect to the genomes from other coronavirus strains, and identifying the changes in the molecular properties due to conformational flexibility in the spike protein
We investigated the variability in the entire sequence of the spike protein, focusing on the regions that showed low-variability in the structure (Figure 2)
Summary
The global pandemic developing from December 2019 by a strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19) disease. This emergent variant adds to the additional coronavirus strains that can infect humans including human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1), SARS-CoV, human coronavirus 229E (HCoV-229E), human coronavirus NL63 (HCoV-NL63), and human coronavirus NL63 (HCoV-NL63) [1,2,3,4,5,6]. Severe acute respiratory syndrome CoV (SARS-CoV) outbreaks have emerged previously creating an epidemic [2,4,9,10,11,12,13]. The data obtained from WHO (08/May/2020) suggest that the virus has caused 3,759,967 infections, 259,474 deaths, and it has affected over 200 countries
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
