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Substituent Effects on Electronic Properties and Acetylcholinesterase Inhibitory Potential of Donepezil Analogues: A DFT, Molecular Docking, and ADMET Study with Dynamics Validation of the Lead Candidate
Ejaz MM, Iftikhar H, Al-Namshah K, Khan S, Ashraf S, Meer N, Riaz M, Saleem M et al.. Research Square, 2026-10-05
Topic: Drug trials: efficacy and safety
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the leading cause of dementia in older people. Donepezil is an acetylcholinesterase inhibitor used for symptomatic management of AD. Due to its high efficacy, low hepatic toxicity, prolonged half-life, and enhanced bioavailability, it was used as a reference. In this study, a series of donepezil derivatives (MH-1 to MH-5) were designed through structural modification at the benzyl moiety and systematically investigated along with the reference using density functional theory, time-dependent DFT, molecular docking, and in silico pharmacokinetics analysis. The geometry optimization and electronic structure calculations were performed using the B3LYP/6-311G (d, p) level. Frontier molecular orbital analysis indicated reduced energy in MH-1 and MH-2 , while the optical study shows that all derivatives (MH-1 to MH-5) demonstrate a bathochromic shift. The molecular docking of all derivatives and the reference against the acetylcholinesterase receptor 4EY7 indicates strong predicted affinities, where MH-1 , MH-2 , and MH-4 show binding energy equivalent to the reference (-12.2 kcal/mol). A 300 ns molecular dynamics simulation of the AChE MH-4 complex showed a stable trajectory, as indicated by RMSD/RMSF profiles. Binding free energy calculated using MM-GBSA combined with the Interaction Entropy approximation yielded ΔG = -13.04 ± 3.73 kcal/mol, confirming favourable and thermodynamically stable binding. Moreover, the results of the ADME analysis indicated good oral absorption and blood-brain barrier penetration. Toxicity assessment predicted favourable safety profiles for most of the derivatives, except for a few that show potential concerns. In summary, all these results indicate that MH-4 has an encouraging physicochemical and computationally predicted bioactive profile for anti-Alzheimer drug development.
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APA 7th
Ejaz, M. M., Iftikhar, H., Al-Namshah, K., Khan, S., Ashraf, S., Meer, N., et al. (2026). Substituent Effects on Electronic Properties and Acetylcholinesterase Inhibitory Potential of Donepezil Analogues: A DFT, Molecular Docking, and ADMET Study with Dynamics Validation of the Lead Candidate. Research Square. https://doi.org/10.21203/rs.3.rs-11082767/v1
Vancouver
Ejaz MM, Iftikhar H, Al-Namshah K, Khan S, Ashraf S, Meer N, et al. Substituent Effects on Electronic Properties and Acetylcholinesterase Inhibitory Potential of Donepezil Analogues: A DFT, Molecular Docking, and ADMET Study with Dynamics Validation of the Lead Candidate. Research Square. 2026. doi:10.21203/rs.3.rs-11082767/v1.
BibTeX
@article{ejaz2026-f06e02fb,
author = {Ejaz, M. M. and Iftikhar, H. and Al-Namshah, K. and Khan, S. and Ashraf, S. and Meer, N. and Riaz, M. and Saleem, M. and others},
title = {{Substituent Effects on Electronic Properties and Acetylcholinesterase Inhibitory Potential of Donepezil Analogues: A DFT, Molecular Docking, and ADMET Study with Dynamics Validation of the Lead Candidate}},
journal = {Research Square},
year = {2026},
doi = {10.21203/rs.3.rs-11082767/v1},
url = {https://doi.org/10.21203/rs.3.rs-11082767/v1}
}
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Key findings
- Moreover, the results of the ADME analysis indicated good oral absorption and blood-brain barrier penetration.
- In summary, all these results indicate that MH-4 has an encouraging physicochemical and computationally predicted bioactive profile for anti-Alzheimer drug development.
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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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