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<p>Protein Disulfide Isomerase (PDI) is a key enzyme in the endoplasmic reticulum (ER), crucial for the proper folding of proteins that require disulfide bonds for stability and function. As nascent proteins are synthesized in the ER, PDI catalyzes the formation, isomerization and rearrangement of disulfide bonds, ensuring correct protein folding and structural integrity. Additionally, PDI acts as a molecular chaperone, stabilizing partially folded proteins and preventing misfolded protein aggregation that is critical in maintaining cellular homeostasis. Given its central role in protein folding and quality control, PDI also interacts with the unfolded protein response aiding in cellular adaptation to stress. Activation of PDI would aid in reducing ER stress associated protein misfolding, involved in many disease pathologies. With this insight, the present study aims to screen for small molecule agonists through core hopping approach for enhancing PDI activity thereby to improve the efficiency of native protein folding. Core hopping was performed with a known PDIA3 activator to generate novel analogues, followed by pharmacophore modeling and virtual screening against ER Stress, Natural Product, Bioactive Compound and Flavonoid libraries to discover the potential small molecules that could activate PDI. Structure-based docking was conducted using Glide in HTVS, SP and XP. Binding affinity was further refined by MM-GBSA ΔG bind calculations and dynamics simulations were performed for the top hits using GROMACS to assess structural stability and interaction dynamics. This integrated approach led to the identification of PDIA3 agonists, mainly Typhaneoside, Oroxin B and Salvianolic acid B as therapeutic promise to alleviate ER stress associated protein misfolding.</p>

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Identification of potent PDIA3 small molecule agonists via structure- and ligand-based drug discovery: a targeted approach to mitigate ER stress associated protein misfolding

  • 期刊论文

  • 发表日期：

    2026年2月13日

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  • Sinduja Gunasekaran,
  • Preethi Saravanan,
  • Surabhi Gupta,
  • Hemamalini Vedagiri

摘要

Protein Disulfide Isomerase (PDI) is a key enzyme in the endoplasmic reticulum (ER), crucial for the proper folding of proteins that require disulfide bonds for stability and function. As nascent proteins are synthesized in the ER, PDI catalyzes the formation, isomerization and rearrangement of disulfide bonds, ensuring correct protein folding and structural integrity. Additionally, PDI acts as a molecular chaperone, stabilizing partially folded proteins and preventing misfolded protein aggregation that is critical in maintaining cellular homeostasis. Given its central role in protein folding and quality control, PDI also interacts with the unfolded protein response aiding in cellular adaptation to stress. Activation of PDI would aid in reducing ER stress associated protein misfolding, involved in many disease pathologies. With this insight, the present study aims to screen for small molecule agonists through core hopping approach for enhancing PDI activity thereby to improve the efficiency of native protein folding. Core hopping was performed with a known PDIA3 activator to generate novel analogues, followed by pharmacophore modeling and virtual screening against ER Stress, Natural Product, Bioactive Compound and Flavonoid libraries to discover the potential small molecules that could activate PDI. Structure-based docking was conducted using Glide in HTVS, SP and XP. Binding affinity was further refined by MM-GBSA ΔG bind calculations and dynamics simulations were performed for the top hits using GROMACS to assess structural stability and interaction dynamics. This integrated approach led to the identification of PDIA3 agonists, mainly Typhaneoside, Oroxin B and Salvianolic acid B as therapeutic promise to alleviate ER stress associated protein misfolding.