Structure-Based Drug Design to Discover Potential Hit Molecules for the Trim71 protein to prevent Congenital Hydrocephalus

Congenital Hydrocephalus (CH) is a neurodevelopmental disorder characterized by the excessive accumulation of cerebrospinal fluid (CSF) in the brain’s ventricles. Current treatments, such as neurological shunting, pose significant risks and fail to address the underlying molecular causes, underscoring the urgent need for targeted therapeutic solutions. Recent studies have found gain-of-function mutations in the TRIM71 gene that cause abnormal binding of the TRIM71 protein to key mRNAs like lsd1 and Ctnnb1, disrupting neural differentiation. In our study, we aimed to identify potential TRIM71 inhibitors using structure-based drug design of known E3 ubiquitin ligase inhibitors. Utilizing molecular modeling tools, including Accelera’s PlayMolecule platform, DockThor, and Schrödinger’s Maestro suite, we screened and analyzed binding interactions of various compounds against the TRIM71 NHL domain (PDB: 7QRX). Our findings revealed promising candidates, with one compound exhibiting an excellent binding energy score (-30.29 kcal/mol) and favorable interactions with key residues such as Arg625, Phe766, Trp704, and Arg751. Additionally, pharmacokinetic assessments using SwissADME confirmed that Compound 5 possesses good blood-brain barrier permeability and adheres to Lipinski’s rule of five, indicating strong drug-likeness. These results highlight the potential of TRIM71-specific inhibitors in addressing the molecular pathology of CH. Future research should focus on experimental validation of these compounds through biochemical assays and in vivo studies to confirm their effectiveness in preventing CSF accumulation and supporting normal neural development in CH patients.