Current drug targets · 2026
Sulfamethoxazole Attenuates Aluminum-induced Cognitive Impairment: In silico Evidence for BACE1 Interaction and In vivo Behavioral Assessment.
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Altaf Aisha, Arif Mehreen, Inam Wali, Abbas Ghulam, Mahmood Wajahat
Аннотация
INTRODUCTION/OBJECTIVE: BACE1 (Beta-Site Amyloid precursor protein-cleaving enzyme is a rate-limiting aspartic protease responsible for beginning Amyloid-β (Aβ) peptide synthesis, the major neurotoxic characteristic of Alzheimer's Disease (AD). Repurposing drugs with known safety profiles and Blood-Brain Barrier (BBB) permeability is a practical approach to treating AD. The current work combined in silico and in vivo approaches to investigate Sulfamethoxazole (SMZ) as a potential BACE1-interacting compound.
METHODS: Molecular docking of sulfamethoxazole to the BACE1 crystal structure (PDB: 1FKN) was done using AutoDock Vina. Female Sprague-Dawley rats (n = 6/group) received AlCl3 (500 mg/kg, i.g.) for 30 days to induce cognitive impairment, while SMZ (0.5, 1.0, and 1.5 mg/kg) was coadministered with AlCl3 for 30 days. On Days 31-36, locomotor activity assessments and the Morris Water Maze (MWM) were used to measure neurocognitive function.
RESULTS: Docking revealed prominent hydrogen-bond interactions between SMZ's sulfonamide oxygen atoms and the Tyr71, Asp228, and Thr72 residues, with the isoxazole ring occupying the hydrophilic S2 pocket of BACE1. Molecular docking analysis indicated a favorable interaction between SMZ and BACE1, suggesting BACE1 as a potential molecular target. In vivo, SMZ dosedependently reversed AlCl3-induced cognitive decline: reduced escape latency (F(1,27) = 117.0; p < 0.0001) and increased time spent in the platform quadrant (F(13.21; 6,6) = p < 0.05). Locomotor activity was unaffected (F(1.150; 3.24); p > 0.05), confirming the absence of CNS stimulation.
DISCUSSION: The findings provide preliminary computational and behavioral evidence supporting further investigation of SMZ in cognitive dysfunction. However, docking predictions do not establish direct BACE1 inhibition, and biochemical validation was not performed.
CONCLUSION: SMZ attenuated AlCl3-induced cognitive impairment in rats and demonstrated a favorable predicted interaction with BACE1. Further studies are required to validate the proposed molecular mechanism and determine the therapeutic relevance of SMZ in cognitive dysfunction.
METHODS: Molecular docking of sulfamethoxazole to the BACE1 crystal structure (PDB: 1FKN) was done using AutoDock Vina. Female Sprague-Dawley rats (n = 6/group) received AlCl3 (500 mg/kg, i.g.) for 30 days to induce cognitive impairment, while SMZ (0.5, 1.0, and 1.5 mg/kg) was coadministered with AlCl3 for 30 days. On Days 31-36, locomotor activity assessments and the Morris Water Maze (MWM) were used to measure neurocognitive function.
RESULTS: Docking revealed prominent hydrogen-bond interactions between SMZ's sulfonamide oxygen atoms and the Tyr71, Asp228, and Thr72 residues, with the isoxazole ring occupying the hydrophilic S2 pocket of BACE1. Molecular docking analysis indicated a favorable interaction between SMZ and BACE1, suggesting BACE1 as a potential molecular target. In vivo, SMZ dosedependently reversed AlCl3-induced cognitive decline: reduced escape latency (F(1,27) = 117.0; p < 0.0001) and increased time spent in the platform quadrant (F(13.21; 6,6) = p < 0.05). Locomotor activity was unaffected (F(1.150; 3.24); p > 0.05), confirming the absence of CNS stimulation.
DISCUSSION: The findings provide preliminary computational and behavioral evidence supporting further investigation of SMZ in cognitive dysfunction. However, docking predictions do not establish direct BACE1 inhibition, and biochemical validation was not performed.
CONCLUSION: SMZ attenuated AlCl3-induced cognitive impairment in rats and demonstrated a favorable predicted interaction with BACE1. Further studies are required to validate the proposed molecular mechanism and determine the therapeutic relevance of SMZ in cognitive dysfunction.