Network‐Based In Silico Identification of Potential Natural Modulators Targeting IQSEC2 and Small GTPase Signaling in Rare Neurodevelopmental Disorders

IQSEC2 (IQ motif and SEC7 domain-containing protein 2) is a rare X-linked genetic disorder associated with intellectual disability, epilepsy, and synaptic dysfunction. No targeted pharmacological treatments are currently available. IQSEC2 functions as a guanine nucleotide exchange factor (GEF) regulating ADP-ribosylation factors (ARFs), particularly ARF6, a key regulator of synaptic vesicle trafficking and neuronal signaling. In this study, we performed in silico molecular docking to evaluate the binding potential of two natural compounds, Polydatin and Amentoflavone, against ARF isoforms (ARF1–ARF6), IQSEC2, IQSEC1, and Ras-related Rab/Ras GTPases. Polydatin demonstrated strong binding affinity to ARF6 (−9.1 kcal/mol) and favorable interactions with IQSEC2 (−7.6 kcal/mol) and IQSEC1 (−7.6 kcal/mol). Amentoflavone exhibited even stronger binding to multiple ARFs and IQSEC proteins, with particularly high affinity for ARF3 (−9.7 kcal/mol) and IQSEC2 (−9.5 kcal/mol). Polydatin also showed significant interactions with Rab and Ras family proteins, including Rab-4A, Rab-5A, Rab-6B, Rab-18, Rab-31, and HRas (−9.6 to −10.5 kcal/mol), suggesting network-level modulation.These findings indicate that both Polydatin and Amentoflavone are computationally plausible probes for experimental studies on IQSEC2 dysfunction, with potential to modulate the IQSEC2–ARF6 axis and associated GTPase signaling. These results remain predictive and require in vitro and in vivo validation, but they provide a strong rationale for prioritizing these natural compounds in IQSEC2-related research. Future studies should include cell-based ARF6/IQSEC2 assays.