Simultaneous Modulation of Amyloidogenesis, Tau Signaling, and Apoptosis: An In-Silico Multi-Target Strategy for Alzheimer's Disease

Authors

• Rutweek Rajendra Kulkarni¹

• Gajendra Choudhary, PhD²

• Ajay Prakash³˒¹

• Bikash Medhi³˒¹

Affiliations

1. Department of Pharmacology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

2. Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

3. Department of Pharmacology, PGIMER, Chandigarh, India

INTRODUCTION

• Alzheimer's disease is characterized by:

  • Amyloid-β accumulation

  • Tau hyperphosphorylation

  • Synaptic dysfunction

  • Neuronal apoptosis

• Current FDA-approved therapies mainly target individual pathological mechanisms and provide only symptomatic benefit.

• Multi-target directed ligands (MTDLs) capable of simultaneously modulating multiple disease pathways may provide superior therapeutic efficacy.

• This study aimed to identify a brain-penetrant multi-target small molecule against four major Alzheimer's disease targets:

  • BACE1 (3VF3)

  • GSK-3β (7B6F)

  • PKA (4UJI)

  • Caspase-3 (AF-P42574-F1)

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METHODS

Identification of Lead Compound

• Approximately 500,000 compounds were screened against four Alzheimer's disease therapeutic targets.

• BBB filtering reduced the library to 45 promising candidates.

• Cross-target screening identified 16 common ligands.

• LAS512463592 demonstrated the highest overall affinity across all four proteins.

Molecular Dynamics Simulation

Parameters evaluated:

• RMSD

• RMSF

  • Low residue fluctuations

  • Stable binding pocket interactions

• Radius of Gyration (Rg)

RESULTS

Docking and MMGBSA Results

Target	Docking Score (kcal/mol)	MMGBSA (kcal/mol)
BACE1	−9.33	−40.60
GSK-3β	−8.14	−50.80
Caspase-3	−7.92	−46.69
PKA	−9.67	−49.14

RMSD (nm)

Protein	APO	LAS	Control
BACE1	0.133 ± 0.017	0.141 ± 0.021	0.132 ± 0.021
GSK-3β	0.416 ± 0.059	0.303 ± 0.056	0.275 ± 0.036
Caspase-3	0.822 ± 0.101	1.068 ± 0.198	0.782 ± 0.107
PKA	0.218 ± 0.033	0.175 ± 0.024	0.173 ± 0.026

RMSF (nm)

Protein	APO	LAS	Control
BACE1	0.075 ± 0.036	0.079 ± 0.044	0.079 ± 0.039
GSK-3β	0.114 ± 0.081	0.136 ± 0.079	0.126 ± 0.089
Caspase-3	0.171 ± 0.194	0.312 ± 0.331	0.234 ± 0.221
PKA	0.090 ± 0.043	0.084 ± 0.042	0.098 ± 0.036

Radius of Gyration (Rg) (nm)

Protein	APO	LAS	Control
BACE1	2.122 ± 0.008	2.119 ± 0.010	2.138 ± 0.010
GSK-3β	2.148 ± 0.011	2.159 ± 0.013	2.185 ± 0.014
Caspase-3	1.920 ± 0.040	1.965 ± 0.100	2.018 ± 0.040
PKA	2.070 ± 0.010	2.050 ± 0.008	2.055 ± 0.010

CONCLUSIONS

• LAS512463592 was identified as a promising multi-target directed ligand against four key Alzheimer's disease proteins.

• Docking and MMGBSA analyses demonstrated favorable binding affinity across:

  • BACE1

  • GSK-3β

  • PKA

  • Caspase-3

• Molecular dynamics simulations confirmed stable protein–ligand complexes with minimal conformational fluctuations.

• These findings support LAS512463592 as a potential disease-modifying candidate for Alzheimer's disease.

• Experimental in-vitro and in-vivo validation is warranted.

HIGHLIGHTS

• Alzheimer's disease requires therapies targeting multiple pathological pathways rather than a single mechanism.

• HTVS of approximately 500,000 ASINEX compounds identified LAS512463592 as a common inhibitor of BACE1, GSK-3β, PKA, and Caspase-3.

• LAS512463592 demonstrated strong binding affinity, BBB permeability, and stable protein–ligand interactions during molecular dynamics simulations.

• The compound represents a promising multi-target disease-modifying candidate for Alzheimer's disease requiring further biological validation.

REFERENCES

1. Alzheimer's Association. 2024 Alzheimer's disease facts and figures. Alzheimers Dement. 2024;20(5):3708–3821.

2. Hampel H, Hardy J, Blennow K, Chen C, Perry G, Kim SH, et al. The amyloid-β pathway in Alzheimer's disease. Nat Rev Drug Discov. 2021;20(8):630–656.

3. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, et al. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004;47(7):1739–1749.

4. Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, Lindahl E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015;1–2:19–25.

CONTACT

Mr. Rutweek Rajendra Kulkarni

• Phone: +91 9309931100

• Email: kulkarnirutweek2000@gmail.com