Computational Prioritization of Compounds Targeting Mutation-Specific Perturbations of MeCP2–DNA Recognition

Missense variants in the methyl-CpG-binding domain (MBD) of MeCP2 are associated with Rett syndrome, yet their molecular effects on protein stability and DNA recognition remain incompletely understood. Here, we integrated structural mapping, energetic prediction, molecular dynamics (MD) simulations, and virtual screening to investigate 80 ClinVar-reported MeCP2 MBD missense variants associated with Rett syndrome and mapped to structurally resolved MBD residues. The variants were distributed mainly across the protein interior and protein–DNA interface. Energy predictions suggested that most variants were destabilizing or produced less favorable MeCP2–DNA binding energetics. MD simulations of eight representative variants revealed mutation-specific changes in conformational dynamics, local flexibility, hydrogen-bond networks, and binding energetics. A two-stage virtual-screening workflow targeting the Arg133Cys-centered MeCP2–DNA interface prioritized five FDA-approved compounds. Subsequent MD simulations further prioritized DB00694 and DB06237 based on retention at the target interface, increased numbers of persistent protein–DNA hydrogen bonds, and more favorable MeCP2–DNA interaction energetics. Overall, these results provide a molecular framework for understanding mutation-specific perturbations of MeCP2–DNA recognition and prioritize compounds for subsequent experimental evaluation.