Molecular modeling to simulation: insights into Gaussian QSAR, molecular docking, and DFT for identification of HDAC3 inhibitors for neurocognitive vascular dementia

Topic: Brain proteins, microglia and lab models

Vascular dementia is the second most common form of dementia. It is characterized by reduced blood flow in the cerebral cortex due to neurodegeneration and neuroinflammation. Almost 10 crore people will be suffering from it by 2030. Still, there are no therapeutics reported for the treatment of neurocognitive vascular dementia. Hence, we have explored an epigenetic pathway for the targeted inhibition of histone deacetylase 3 (HDAC3) that can further cure the neurocognitive impairment. In the present study, we have incorporated in silico methodologies for small-molecule inhibitor screening. The methodologies include multi-model pharmacophore development, validation, virtual screening by HDAC3 targeted docking and dynamics simulation, quantum chemical analysis, and ADMET properties. After the virtual screening, the best two compounds were selected according to the docking score, MM/GBSA scoring, and IFD. The top two hits—57402 and 46381 represented interactions with zinc-binding and amino acids such as HIE172 and HIE135 GLY143, and ASP93 residues compared with RGFP966. Furthermore, the density function theory study was employed to understand the reactivity and stability of the compounds, and quantum chemical properties relevant to drug design were compared with standard RGFP966. Following the molecular dynamics simulation and ADMET analysis, which evaluates how a substance is absorbed, distributed, metabolized, and excreted, along with its toxicity, the two hit compounds—57402 and 46381 showed superior binding scores and targeted inhibition of HDAC3 by zinc chelation. Therefore, the study is of great significance in the quest for new molecules for the treatment of vascular dementia targeting HDAC3.

Key findings

• The top two hits—57402 and 46381 represented interactions with zinc-binding and amino acids such as HIE172 and HIE135 GLY143, and ASP93 residues compared with RGFP966.
• Furthermore, the density function theory study was employed to understand the reactivity and stability of the compounds, and quantum chemical properties relevant to drug design were compared with standard RGFP966.

Why it matters

This is a computer-based (in silico) study that screened small molecules for inhibiting HDAC3 as a possible approach to vascular dementia, selecting two top compounds based on docking and simulation. It is early computational work and no compound has been tested in patients, so it does not yet show any treatment, cure or prevention.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/s41598-025-28304-y
• PubMed: 41326481
• Original source →
• Free full text: Scientific Reports →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{halder2025-41326481,
  author  = {Halder, Debojyoti and Banerjee, Suvankar and Biswas, Swati and Adhikari, Nilanjan and Ghosh, Balaram},
  title   = {{Molecular modeling to simulation: insights into Gaussian QSAR, molecular docking, and DFT for identification of HDAC3 inhibitors for neurocognitive vascular dementia}},
  journal = {Scientific Reports},
  year    = {2025},
  doi     = {10.1038/s41598-025-28304-y},
  pmid    = {41326481},
  url     = {https://doi.org/10.1038/s41598-025-28304-y}
}

Related studies in Lewy body dementia

• Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study Alzheimer's & dementia : the journal of the Alzheimer's Association · 2014-08-15 · usefulness score 62/100
• A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study The Lancet. Neurology · 2011-12-07 · usefulness score 61/100
• Human iPSC-based modeling of late-onset disease via progerin-induced aging Cell stem cell · 2013-12-01 · usefulness score 53/100
• Modeling Parkinson's Disease With the Alpha-Synuclein Protein Frontiers in pharmacology · 2020-04-23 · usefulness score 51/100
• Recent developments of HDAC inhibitors: Emerging indications and novel molecules British journal of clinical pharmacology · 2021-05-27 · usefulness score 49/100
• Dementia and PDE5 inhibitors: A retrospective cohort study of veterans Research Square · 2026-10-13 · usefulness score 16/100

Similar studies

• Molecular Mechanisms of Vascular Dementia: What Can Be Learned from Animal Models of Chronic Cerebral Hypoperfusion? 2017 · Inflammation and the immune system
• Identifying natural inhibitors against FUS protein in dementia through machine learning, molecular docking, and dynamics simulation 2025 · Digital health tools
• Linking Molecular Pathways and Large-Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer's Disease 2019 · Long-term cohort studies
• Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer's Disease 2017 · Disease mechanisms
• A next-generation HDAC6 inhibitor for amyotrophic lateral sclerosis and frontotemporal dementia 2025 · Lewy body dementia
• NLRP3 Inflammasome in Vascular Dementia: Regulatory Mechanisms, Functions, and Therapeutic Implications: A Comprehensive Review 2025 · Lewy body dementia

More on Lewy body dementia

• A review that covers this ground The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies Experimental & molecular medicine · 2020-10-13 · usefulness score 51/100
• Newest in this subject Frequency-Resolved Connectivity Graphs for EEG-Based Classification of Alzheimer and Frontotemporal Dementia bioRxiv · 2026-10-22 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Decoding Dementia from Sweat: A Proof-of-Concept Label-Free Raman Fingerprinting of EVs medRxiv · 2026-10-01 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Lewy body dementia →