In-Silico Drug Designing & Computational Study of Various Novel-Analogues against Novel Therapeutic Targets in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) treatment and management significantlyremain an unaddressed medical challenge, with limited disease-modifying therapeutic options. In this study, we employed an integrated in silico computational strategy to identify and characterize novel compound analogues with potential anti-Alzheimer’s activity. A rational analogue design approach was applied to a selected lead scaffold, followed by virtual screening to evaluate target binding affinity against key AD-associated proteins implicated in amyloidogenic processing, tau pathology, and neuroinflammation. Molecular docking and binding interaction analyses were conducted to elucidate structure–activity relationships and prioritize high-affinity candidates. Top-ranking analogueswere further assessed using molecular dynamics simulations to examine complex stability and conformational behaviour under physiological conditions. Several novel analoguesdemonstrated improved binding affinity, favourable interaction patterns, and enhanced predicted pharmacological properties compared to the parent compound. These findings highlight promising lead candidates for further optimization and experimental validation andprove the utility of computational approaches in accelerating early-stage drug discovery for Alzheimer’s disease.

Introduction

Alzheimer’s disease (AD) is a complex neurodegenerative disorder involving multiple interconnected biochemical pathways beyond traditional amyloid-focused mechanisms. While conventional therapies mainly target amyloid precursor protein (APP) processing through β- and γ-secretases, emerging research highlights the importance of alternative molecular targets linked to neuroinflammation, oxidative stress, synaptic dysfunction, and lipid metabolism.

Recent studies identify phospholipases, particularly Phospholipase D3 (PLD3) and phospholipase A2, as promising targets due to their roles in APP metabolism, neuroinflammation, and oxidative stress. Genetic evidence, including rare PLD3 variants associated with late-onset AD, supports their involvement in disease progression. Molecular docking and interaction analyses demonstrate that selected small-molecule compounds can stably bind to PLD3, suggesting potential inhibitory activity.

Another critical pathway implicated in AD is the kynurenine pathway, regulated by indoleamine 2,3-dioxygenase (IDO) enzymes. Chronic neuroinflammation in AD leads to persistent IDO activation, altered tryptophan metabolism, accumulation of neurotoxic metabolites, and increased neuronal vulnerability. Docking studies indicate effective binding of candidate compounds to IDO1, supporting IDO inhibition as a disease-modifying therapeutic strategy.

Additionally, soluble epoxide hydrolase (sEH) has emerged as a key target linking lipid signaling, vascular regulation, and inflammation. Elevated sEH activity reduces neuroprotective epoxy fatty acids and increases pro-inflammatory metabolites, contributing to neurodegeneration. Inhibition of sEH has been shown to reduce inflammation, improve cerebral blood flow, lower amyloid burden, and enhance cognitive function.

Conclusion

The study emphasized the significance of docking analysis involving novel compounds targeting newly identified proteins that are increasingly associated with neurodegenerative diseases such as Alzheimer’s. By focusing on these novel targets, the research not only broadens the understanding of molecular interactions critical to disease progression but also suggests potential therapeutic strategies. These targets may serve as adjuncts to existing standard treatments, offering palliative benefits and possibly enhancing overall efficacy. This approach opens new pathways for drug development and encourages further exploration of molecular mechanisms underlying neurodegeneration. Docking analysis targeting novel proteins implicated in neurodegenerative diseases such as Alzheimer’s represents a pivotal advancement in therapeutic research. By identifying and characterizing these previously unexplored molecular targets, the study enhances our comprehension of the intricate protein-ligand interactions that drive disease pathology. This detailed understanding facilitates the rational design of compounds with improved specificity and efficacy, potentially overcoming limitations associated with conventional treatments. Importantly, these novel targets provide opportunities to intervene at various stages of neurodegeneration, which could slow or modify disease progression rather than merely alleviating symptoms. Furthermore, integrating these newly identified targets into therapeutic strategies may complement existing standard-of-care treatments, thereby offering synergistic effects that enhance patient outcomes. The adjunctive use of novel compounds could improve palliative care by addressing molecular pathways not targeted by current drugs, ultimately contributing to a more holistic management of neurodegenerative disorders. This approach also encourages ongoing exploration of the molecular mechanisms underpinning these diseases, fostering innovation in drug discovery and development. Collectively, these efforts open promising avenues for creating more effective and personalized interventions against Alzheimer’s and related neurodegenerative conditions.

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Copyright

Copyright © 2026 Debajyoti Sarkar, Sk Shamsuddin , Najmul Islam Mondal, Sulagna Ray. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.