The Effect of ACE2 Inhibitor MLN-4760 on the Interaction of SARS-CoV-2 Spike Protein with Human ACE2: A Molecular Dynamics Study
Bibliographic record
Abstract
A previous study shows that an ACE2 enzymatic activity inhibitor efficiently blocks the interaction of SARS-CoV spike protein with human ACE2 and may be effective in preventing the coronavirus membrane fusion and entry to human cells. The report suggests that potent ACE2 inhibitors can be used to treat hypertension as well as for controlling SARS-CoV infection. We here studied the effect of a selective and highly potent ACE2 inhibitor (MLN-4760) on the interaction of the SARS-CoV-2 spike receptor-binding domain (RBD) with human ACE2 by molecular dynamics (MD) simulation. To this end, we docked the RBD of SARS-CoV-2 to the human native ACE2 and the ACE2 complexed with MLN-4760, and analyzed the dynamics, protein-protein and ligand-protein interactions of the complexes by MD simulation in a simulated biological condition for 100 ns. Analyzing crystallographic structures of SARS-CoV-2 and SARS-CoV RBDs in the complexes with human ACE2 showed that RBD of SARS-CoV-2 binds to ACE2 with a higher affinity than that of SARS-CoV. Results also revealed that MLN-4760 binds to ACE2 at the enzymatic active site with a high affinity and significantly alters the ACE2 protein conformation. MLN-4760 also changes the binding site and the residues involved in hydrogen and hydrophobic binding between RBD and ACE2, however, it had no major effect on the binding affinity of the interaction between RDB and ACE2. Interestingly, binding RBD to the ACE2 complexed with MLN-4760 abrogated the inhibitory effect of MLN-4760 and rescued the conformation of the ACE2 enzymatic site by reforming the closed conformation to the open native conformation. This was due to the disassociation of MLN-4760 from the enzymatic active site of the ACE2 in the result of RBD binding. Overall, these results show that MLN-4760 does neither block nor increase the binding of SARS-CoV-2 spike RBD to human ACE2 and probably had no effect on the viral entry. However, binding the spike protein to ACE2 can rescue the enzymatic function of ACE2 from its inhibitor.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".