In silico analysis of SARS-CoV-2 spike protein N501Y and N501T mutation effects on human ACE2 binding.

The SARS-CoV-2 is an RNA-based virus and the most vital step of its survival is the attachment to hACE2 through its spike protein. Although SARS-CoV-2 has the ability to maintain high accurate replication and it can be accepted as a low mutation risked virus, it already showed more than nine thousand mutations in spike protein, of which 44 mutations are located within a 3.2 Å interacting distance from the hACE2 receptor. Mutations on spike protein, N501Y and N501T raised serious concerns for higher transmissibility and resistance towards current vaccines. In the current study, the mutational outcomes of N501Y and N501T on the hACE2-SARS CoV-2 spike protein complexation were analyzed by employing all-atom classic molecular dynamics (MD) simulations. These simulations revealed that both N501Y and N501T mutations increased the binding strength of spike protein to the host hACE2, predicted by binding free energy analysis via MM/GBSA rescoring scheme. This study highlights the importance of energy-based analysis for identifying mutational outcomes and will shed light on handling long-term and effective treatment strategies including repurposing anti-viral drugs, anti-SARS-CoV-2 antibodies, vaccines, and antisense based-therapies.

Computational analysis of functional monomers used in molecular imprinting for promising COVID-19 detection.

Today, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently caused a severe outbreak worldwide. There are still several challenges in COVID-19 diagnoses, such as limited reagents, equipment, and long turnaround times. In this research, we propose to design molecularly imprinted polymers as a novel approach for the rapid and accurate detection of SARS-CoV-2. For this purpose, we investigated molecular interactions between the target spike protein, receptor-binding domain of the virus, and the common functional monomers used in molecular imprinting by a plethora of computational analyses; sequence analysis, molecular docking, and molecular dynamics (MD) simulations. Our results demonstrated that AMPS and IA monomers gave promising results on the SARS-CoV-2 specific TEIYQAGST sequence for further analysis. Therefore, we propose an epitope approach-based synthesis route for specific recognition of SARS-CoV-2 by using AMPS and IA as functional monomers and the peptide fragment of the TEIYQAGST sequence as a template molecule.

Comparison of clinically approved molecules on SARS-CoV-2 drug target proteins: a molecular docking study.

The new type of coronavirus, SARS-CoV-2 has affected more than 22.6 million people worldwide. Since the first day the virus was spotted in Wuhan, China, numerous drug design studies have been conducted all over the globe. Most of these studies target the receptor-binding domain of spike protein of SARS-CoV-2, which is known to bind to the human ACE2 receptor and SARS-CoV-2 main protease, vital for the virus' replication. However, there might be a third target, human furin protease, which cleaves the virus' S1-S2 domains playing an active role in its entry into the host cell. In this study, we docked five clinically used drug molecules, favipiravir, hydroxychloroquine, remdesivir, lopinavir, and ritonavir onto three target proteins, the receptor-binding domain of SARS-CoV-2 spike protein, SARS-CoV-2 main protease, and human furin protease. Results of molecular docking simulations revealed that human furin protease might be targeted by COVID-19. Remdesivir, a nucleic acid derivative, strongly bound to the active site of this protease, suggesting that this molecule can be used as a template for designing novel furin protease inhibitors to fight against the disease. Protein-drug interactions revealed in this study at the molecular level, can pave the way for better drug design for each specific target.