Fact check: What are the molecular mechanisms of ivermectin's interaction with SARS-CoV-2 spike protein?

1. A laboratory signal: experimental assays claim micromolar ivermectin–spike binding

The in vitro analyses summarize experiments using equilibrium dialysis and DARTS that report measurable binding between ivermectin and the SARS‑CoV‑2 spike protein, yielding Ka = 1.22 µM‑1 and Kd = 0.81 µM, figures the authors interpret as evidence of a potential binding mechanism. The experimental report (dated November 16, 2023 in the analysis) frames this as direct biochemical interaction rather than an inference from modeling, and the work is presented as a primary assay demonstrating physical association at low micromolar concentrations. That affinity range implies binding that could be detectable in controlled assays but does not by itself prove functional inhibition of spike–ACE2 interaction or antiviral activity in cells or patients; the analysis cautions that assay conditions, spike construct, and ivermectin formulation heavily influence apparent constants ^[1].

2. Computational models: recurring residue hotspots and predicted energetics

Multiple docking and molecular dynamics studies from early pandemic efforts predict that ivermectin has favorable binding energy and specific contacts on the receptor‑binding domain of the spike, repeatedly implicating LEU492 and GLN493 in hydrogen bonding and residues such as GLY496 and TYR505 in additional stabilizing interactions. Reported binding energies (for example, approximately −9.0 kcal/mol in one 2021 modeling study) and stable trajectories in molecular dynamics are used to argue for a plausible mechanistic basis whereby ivermectin could sterically or allosterically interfere with ACE2 engagement. These computational results are internally consistent across several reports but rely on modeled conformations, scoring functions, and limited sampling, which can overestimate affinity relative to experimental measures ^{[2] [3]}.

3. Reconciling model predictions with experimental affinity: a mixed picture

Comparing the micromolar experimental constants with the docking energetics exposes a common pattern: dockings predict strong, specific contacts, while experiments place binding in a moderate micromolar range. This discrepancy can arise because docking scores translate imperfectly to dissociation constants, and because experimental Kd values depend on protein conformation, glycosylation state, and assay environment. The experimental Kd (~0.81 µM) is broadly compatible with a docking‑predicted favorable interaction but does not confirm that the binding site or mechanism is identical to the residues highlighted in silico. Moreover, experimental evidence reported in 2023 is more direct but still limited to biochemical assays; there is no direct experimental demonstration in these analyses that ivermectin blocks spike binding to ACE2 on cells or prevents viral entry at clinically achievable concentrations ^{[1] [2]}.

4. What the studies omit: physiological concentrations, spike context, and clinical linkage

None of the provided analyses bridges the crucial gap between molecular binding and therapeutic effect. The experimental and computational studies do not establish whether the measured micromolar binding occurs at plasma or tissue concentrations achievable in humans with standard ivermectin dosing, nor do they address spike glycosylation, trimeric architecture, or membrane context that could alter access to predicted binding pockets. The 2021 computational work and later experimental assays do not include cell‑based neutralization or in vivo efficacy correlated with the same mechanistic readouts; therefore, claims that binding implies antiviral benefit are unsupported by these data alone ^{[2] [3] [1]}.

5. Multiple interpretations and potential agendas: modeling enthusiasts vs. experimenters

The corpus shows two distinct camps: computational studies emphasizing mechanistic plausibility and experimental work reporting measurable binding. Modeling papers (mostly 2021) emphasize residue interactions and energetics, which can be used to argue for drug repurposing, while the 2023 biochemical report provides an empirical anchor for binding but remains limited in scope. Readers should note that both approaches can be selectively cited to support efficacy claims; computational predictions are hypothesis‑generating, and biochemical binding is necessary but not sufficient evidence for clinical utility. The analyses provided here do not include randomized clinical data or robust cellular neutralization studies linking the described molecular interactions to clinical benefit ^{[2] [1] [4]}.