In-Silico Optimization of Galanthamine Derivatives: Towards Next-Generation Neuroprotective Agents

Abstract

This investigation delineates the drug–receptor interactions of galantamine derivatives through advanced molecular docking methodologies, underscoring their relevance in contemporary medicinal chemistry. Ten structurally novel galantamine analogues, incorporating the indanone ring system, were synthesized and rigorously characterized via spectral analysis. Docking simulations against human acetylcholinesterase (AChE, PDB ID: 1dx6) revealed consistently favorable binding energies and pronounced affinity for the enzyme’s catalytic pocket, with several derivatives surpassing the inhibitory potential of the parent compound. Critical interactions with residues including Trp86, Tyr124, Ser203, Glu202, Tyr337, Phe338, His447, and Tyr449 were elucidated, emphasizing the indispensability of flexible docking in capturing physiologically relevant conformations. The findings highlight the therapeutic promise of structural modifications to galantamine, particularly in enhancing pharmacological efficacy for Alzheimer’s disease management. By obstructing the peripheral anionic site of AChE, these analogues may attenuate amyloid-β aggregation, a cardinal pathological hallmark of neurodegeneration. Computational modeling thus emerges as a cost-efficient and predictive paradigm for rational drug design, enabling the prioritization of candidate molecules prior to labor-intensive experimental validation. Collectively, the synthesized galantamine derivatives constitute compelling lead scaffolds for the development of next-generation AChE inhibitors with augmented neuroprotective activity. While subsequent in-vitro and in-vivo investigations remain imperative to substantiate therapeutic utility, this work establishes a robust foundation for the strategic advancement of cholinesterase-targeted interventions in neurodegenerative disorders.