Related Experiment Video
Updated: Nov 15, 2025
Engineering Antiviral Agents via Surface Plasmon Resonance
Published on: June 14, 2022
An Active Site Inhibitor Induces Conformational Penalties for ACE2 Recognition by the Spike Protein of SARS-CoV-2
Billy J Williams-Noonan1, Nevena Todorova1, Ketav Kulkarni2
1School of Engineering, RMIT University, Melbourne, Victoria 3001, Australia.
Abstract:
The novel RNA virus, severe acute respiratory syndrome coronavirus II (SARS-CoV-2), is currently the leading cause of mortality in 2020, having led to over 1.6 million deaths and infecting over 75 million people worldwide by December 2020. While vaccination has started and several clinical trials for a number of vaccines are currently underway, there is a pressing need for a cure for those already infected with the virus. Of particular interest in the design of anti-SARS-CoV-2 therapeutics is the human protein angiotensin converting enzyme II (ACE2) to which this virus adheres before entry into the host cell. The SARS-CoV-2 virion binds to cell-surface bound ACE2 via interactions of the spike protein (s-protein) on the viral surface with ACE2. In this paper, we use all-atom molecular dynamics simulations and binding enthalpy calculations to determine the effect that a bound ACE2 active site inhibitor (MLN-4760) would have on the binding affinity of SARS-CoV-2 s-protein with ACE2. Our analysis indicates that the binding enthalpy could be reduced for s-protein adherence to the active site inhibitor-bound ACE2 protein by as much as 1.48-fold as an upper limit. This weakening of binding strength was observed to be due to the destabilization of the interactions between ACE2 residues Glu-35, Glu-37, Tyr-83, Lys-353, and Arg-393 and the SARS-CoV-2 s-protein receptor binding domain (RBD). The conformational changes were shown to lead to weakening of ACE2 interactions with SARS-CoV-2 s-protein, therefore reducing s-protein binding strength. Further, we observed increased conformational lability of the N-terminal helix and a conformational shift of a significant portion of the ACE2 motifs involved in s-protein binding, which may affect the kinetics of the s-protein binding when the small molecule inhibitor is bound to the ACE2 active site. These observations suggest potential new ways for interfering with the SARS-CoV-2 adhesion by modulating ACE2 conformation through distal active site inhibitor binding.
Insights
A novel inhibitor targeting the ACE2 protein could weaken SARS-CoV-2 spike protein binding by up to 1.48-fold. This research explores new therapeutic strategies against the virus by modulating ACE2 conformation.
Area of Science:
- Biochemistry
- Virology
- Computational Biology
Background:
- Severe acute respiratory syndrome coronavirus II (SARS-CoV-2) poses a significant global health threat, necessitating the development of effective antiviral therapies.
- The virus utilizes the human angiotensin converting enzyme II (ACE2) receptor for cell entry, making ACE2 a key target for therapeutic intervention.
- Understanding the molecular interactions between SARS-CoV-2 spike protein and ACE2 is crucial for designing drugs that block viral adhesion.
Purpose of the Study:
- To investigate the impact of an ACE2 active site inhibitor (MLN-4760) on the binding affinity between the SARS-CoV-2 spike protein and ACE2.
- To elucidate the molecular mechanisms underlying any observed changes in binding strength and kinetics.
Main Methods:
- All-atom molecular dynamics simulations were employed to model the interaction between SARS-CoV-2 spike protein, ACE2, and the MLN-4760 inhibitor.
- Binding enthalpy calculations were performed to quantify the changes in binding affinity.
Main Results:
- The binding enthalpy between the SARS-CoV-2 spike protein receptor binding domain (RBD) and ACE2 was reduced by up to 1.48-fold when ACE2 was bound by MLN-4760.
- This reduction in binding strength is attributed to the destabilization of key residue interactions (Glu-35, Glu-37, Tyr-83, Lys-353, Arg-393) between ACE2 and the SARS-CoV-2 RBD.
- Conformational changes, including increased lability of the N-terminal helix and shifts in ACE2 motifs, were observed, potentially affecting binding kinetics.
Conclusions:
- Binding of MLN-4760 to the ACE2 active site can significantly weaken the interaction with the SARS-CoV-2 spike protein.
- Modulating ACE2 conformation through distal active site inhibitors presents a promising therapeutic strategy for interfering with SARS-CoV-2 adhesion.
- These findings offer insights into novel approaches for developing anti-SARS-CoV-2 therapeutics.
More Related Videos
06:39High-throughput Confocal Imaging of Quantum Dot-Conjugated SARS-CoV-2 Spike Trimers to Track Binding and Endocytosis in HEK293T Cells
Published on: April 21, 2022
07:53A Fluorogenic Peptide Cleavage Assay to Screen for Proteolytic Activity: Applications for coronavirus spike protein activation
Published on: January 9, 2019
Related Concept Videos
01:30Antihypertensive Drugs: Angiotensin-Converting Enzyme Inhibitors
02:34Enzymes
Enzyme deficiencies can often translate into life-threatening diseases. For example, a genetic abnormality resulting in the deficiency of the enzyme G6PD...
01:30Enzyme Inhibition
01:13Induced-fit Model
Enzymes exhibit substrate specificity, meaning that they can only bind to certain substrates. This is mainly determined by the shape and chemical...
01:18Indirect-Acting Cholinergic Agonists: Mechanism of Action
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex,...
01:12GPCR Desensitization