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Exploring the Molecular and Biochemical Mechanisms of Aromasin in Modulating COX-2/iNOS for Alzheimer’s Disease-Associated Synaptic Dysfunction: An In Silico Drug Repurposing Study
Baral DS, Verma R.. Research Square, 2026-08-18
Topic: Drug trials: efficacy and safety
Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) are central regulators of synaptic homeostasis, plasticity, and dysfunction during Alzheimer’s disease (AD) progression. Dysregulation of this axis promotes oxidative stress, neuronal injury, impaired synaptic signalling, and cognitive decline. This study aimed to identify a single drug capable of simultaneously modulating the COX-2/iNOS using an in silico drug-repurposing strategy. A library of 3,193 clinically approved compounds was screened, 411 candidates predicted to cross the blood-brain barrier. These compounds were evaluated using molecular docking, ADMET profiling, molecular dynamics simulations, and MM-PBSA free-energy calculations. Aromasin emerged as the most promising candidate, showing strong docking affinities for COX-2 (-9.00 kcal/mol) and iNOS (-7.47 kcal/mol), along with favourable pharmacokinetic properties and predicted CNS safety. MD simulations demonstrated stable protein-ligand complexes, with average RMSD values of ~ 0.09 nm (COX-2) and ~ 0.65 nm (iNOS), supported by RMSF, SASA, hydrogen-bonding, and radius of gyration analyses. PCA indicated ligand-induced stabilization, with the first two eigenmodes capturing ~ 40% of conformational variance. FEL analysis revealed deeper, localized minima upon Aromasin binding, consistent with enhanced thermodynamic stability. MM-PBSA calculations confirmed favourable binding free energies for COX-2 (-24.95 kcal/mol) and iNOS (-21.41 kcal/mol), positioning Aromasin as a promising repurposed modulator for AD-associated synaptic dysfunction. Mechanistically, Aromasin occupied the catalytic pockets through hydrophobic and hydrogen-bond interactions, while dynamic analyses indicated coordinated residue motions and restricted conformational sampling, suggesting that dual target engagement may modulate interconnected inflammatory, oxidative, and nitrosative signalling pathways underlying AD-associated synaptic dysfunction.
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APA 7th
Baral, D. S., & Verma, R. (2026). Exploring the Molecular and Biochemical Mechanisms of Aromasin in Modulating COX-2/iNOS for Alzheimer’s Disease-Associated Synaptic Dysfunction: An In Silico Drug Repurposing Study. Research Square. https://doi.org/10.21203/rs.3.rs-10701602/v1
Vancouver
Baral DS, Verma R. Exploring the Molecular and Biochemical Mechanisms of Aromasin in Modulating COX-2/iNOS for Alzheimer’s Disease-Associated Synaptic Dysfunction: An In Silico Drug Repurposing Study. Research Square. 2026. doi:10.21203/rs.3.rs-10701602/v1.
BibTeX
@article{baral2026-e2e1ba0c,
author = {Baral, D. S. and Verma, R.},
title = {{Exploring the Molecular and Biochemical Mechanisms of Aromasin in Modulating COX-2/iNOS for Alzheimer’s Disease-Associated Synaptic Dysfunction: An In Silico Drug Repurposing Study}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-10701602/v1},
url = {https://doi.org/10.21203/rs.3.rs-10701602/v1}
}
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Key findings
- MD simulations demonstrated stable protein-ligand complexes, with average RMSD values of ~ 0.09 nm (COX-2) and ~ 0.65 nm (iNOS), supported by RMSF, SASA, hydrogen-bonding, and radius of gyration analyses.
- FEL analysis revealed deeper, localized minima upon Aromasin binding, consistent with enhanced thermodynamic stability.
- Mechanistically, Aromasin occupied the catalytic pockets through hydrophobic and hydrogen-bond interactions, while dynamic analyses indicated coordinated residue motions and restricted conformational sampling, suggesting that dual target engagement may modulate interconnected inflammatory, oxidative, and nitrosative signalling pathways underlying AD-associated synaptic dysfunction.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (Research Square) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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