Could Unfold Protein Response Pathway Proteins be a Missing Link in Neuropathic Pain and Alzheimer’s Disease Etiology? — Findings from Computational Studies

Abstract

Background: Neurodegenerative diseases, including Alzheimer’s disease, are characterized by progressive neuronal cell loss and nervous system damage. Neuropathic pain, resulting from traumatic injury to sensory nerves, is closely associated with these neurodegenerative conditions. Endoplasmic reticulum (ER) stress, arising from protein misfolding or accumulation of unfolded proteins, plays a crucial role in maintaining cellular homeostasis through the activation of the unfolded protein response (UPR). Interestingly, the ER stress pathway has emerged as a potential link between neuropathic pain and Alzheimer’s disease. To investigate this link, we selected specific drugs with known mechanisms of action: GSK2606414, an EIF-2[Formula: see text] phosphorylation inhibitor, Valsartan, which down-regulates ER stress-related proteins, Gemigliptin, known to decrease GRP78 expression, and Melatonin, shown to reduce ATF6 mRNA and protein levels. Additionally, Vemurafenib and Obatoclax were chosen as kinase and Bcl2 inhibitors, respectively. Drug selection was based on data from DrugBank and literature, with their structures obtained from the PubChem database. Main methodologies: Our research aims to identify potential therapeutic targets bridging neuropathic pain and Alzheimer’s disease. Using AutoDock v4.2.6, we conducted molecular docking studies, revealing promising drug–target interactions. We further performed molecular dynamic (MD) simulations for 100 ns using the WEBGRO online server to assess drug-target stability. Additionally, we employed Lipinski screening via the SwissADME web server, assessing pharmacokinetic properties and toxicity. Results: Except for ATF4 (with Metformin), all targets showed favorable affinity toward Obatoclax, with binding energies ranging from −5.32 to −7.48 kcal/mol. The XBP1–Obatoclax complex stability is evaluated using MD simulation. The ADMET screening results indicated that the drugs displayed good intestinal absorption (above 30%), making them suitable for oral administration. Importantly, these drugs showed no inhibitory effects against CYP2D6 isozymes expressed in the CNS. Future perspective: Our in silico findings provide valuable evidence and potential leads for further evaluation and confirmation through in vitro research. The data generated from this study may contribute to the development of novel therapeutics targeting both neuropathic pain and Alzheimer’s disease, offering new hope for patients suffering from these debilitating conditions.