Abstract
A rational therapeutic strategy is urgently needed for combating SARS-CoV-2 infection. Viral infection initiates when the SARS-CoV-2 receptor-binding domain (RBD) binds to the ACE2 receptor, and thus, inhibiting RBD is a promising therapeutic for blocking viral entry. In this study, the structure of lead antiviral candidate binder (LCB1), which has three alpha-helices (H1, H2, and H3), is used as a template to design and simulate several miniprotein RBD inhibitors. LCB1 undergoes two modifications: structural modification by truncation of the H3 to reduce its size, followed by single and double amino acid substitutions to enhance its binding with RBD. We use molecular dynamics (MD) simulations supported by ab initio density functional theory (DFT) calculations. Complete binding profiles of all miniproteins with RBD have been determined. The MD investigations reveal that the H3 truncation results in a small inhibitor with a −1.5 kcal/mol tighter binding to RBD than original LCB1, while the best miniprotein with higher binding affinity involves D17R or E11V + D17R mutation. DFT calculations provide atomic-scale details on the role of hydrogen bonding and partial charge distribution in stabilizing the minibinder:RBD complex. This study provides insights into general principles for designing potential therapeutics for SARS-CoV-2.
Highlights
Spike (S) protein of severe acute respiratory syndrome (SARS-CoV-2) virus is an ideal molecular target to develop prophylactics and therapeutics against the ongoing COVID-19 pandemic [1,2,3,4,5]
Vaccinations are the most successful therapeutics [21,22], but alternative treatments are necessary in some cases such as when certain patients are unable to get a vaccination owing to their medical condition, lack of availability, or when vaccine efficacy is compromised by new SARS-CoV-2 variants [23]
We propose that exchanging these amino acid (AA) by other carefully selected AAs may boost the binding affinity of MP3 with receptor-binding domain (RBD)
Summary
Spike (S) protein of severe acute respiratory syndrome (SARS-CoV-2) virus is an ideal molecular target to develop prophylactics and therapeutics against the ongoing COVID-19 pandemic [1,2,3,4,5]. Vaccinations are the most successful therapeutics [21,22], but alternative treatments are necessary in some cases such as when certain patients are unable to get a vaccination owing to their medical condition, lack of availability, or when vaccine efficacy is compromised by new SARS-CoV-2 variants [23]. Besides these concerns, the vaccine candidates and the antibodies rely on the molecular mechanism to interact with pathogens in a way that radically differs from how the pathogen binds its host targets [24]
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.
