Mechanistic exploration of IGF2BP3-mediated m6A dynamics in diabetic retinopathy for therapeutic interventions...

Area of Science:

• Biochemistry and Molecular Biology
• Ophthalmology
• Pharmacology

Background:

• Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) is a key regulator of mRNA processing.
• IGF2BP3 overexpression is linked to cancer and increasingly implicated in diabetic retinopathy (DR), a leading cause of blindness.
• IGF2BP3 promotes angiogenesis and inflammation in DR by regulating vascular endothelial growth factor (VEGF) and other factors.

Purpose of the Study:

• To identify novel small molecule inhibitors targeting IGF2BP3 for the potential treatment of diabetic retinopathy.
• To explore the druggability of IGF2BP3's RNA-binding domains, specifically KH3 and KH4.
• To computationally screen for compounds that can disrupt IGF2BP3's interaction with RNA.

Main Methods:

• High-throughput virtual screening (HTVS) of the ChemDiv database against IGF2BP3's KH4 domain.
• Molecular docking, Density Functional Theory (DFT), and molecular dynamics (MD) simulations to assess binding affinity and stability.
• Analysis of interactions between identified compounds and key residues within the IGF2BP3 KH4 domain.

Main Results:

• The KH4 domain of IGF2BP3 was identified as a promising druggable target.
• Three compounds (Y040-1954, C200-9224, 1761-0723) showed strong binding to the GXXG motif in the KH4 domain.
• MD simulations confirmed the stability of IGF2BP3-inhibitor complexes, with consistent hydrogen bonding involving Ser624, Ser627, and Thr628.

Conclusions:

• The identified compounds have the potential to inhibit IGF2BP3 activity by disrupting its RNA-binding capabilities.
• These inhibitors could block the stabilization of pro-angiogenic and pro-inflammatory mRNAs implicated in DR pathogenesis.
• Further experimental validation and optimization of these compounds may lead to novel therapeutic strategies for diabetic retinopathy.