Virtual Screening, Molecular Dynamics, and Density Functional Theory Identify Piperolein A as a Putative Dual PPARα/γ Modulator Relevant to Radiation‐Induced Cognitive Decline
Radiation‐induced cognitive decline (RICD) is a debilitating late effect of cranial radiotherapy characterized by persistent oxidative stress, neuroinflammation, and impaired hippocampal neurogenesis. Given the established roles of peroxisome proliferator‐activated receptors α and γ (PPARα/γ) in regulating inflammatory and metabolic homeostasis, this study employed a multiscale structure‐based computational workflow to identify potential dual PPARα/γ modulators from IMPPAT database. Hierarchical molecular docking, MM‐GBSA binding‐energy estimation, ADMET filtering, and 100‐ns molecular dynamics (MDs) simulations prioritized two candidate modulators: IMPHY000027 ((E)‐piperolein A) and IMPHY015538. Principal component analysis, free‐energy landscape mapping, and correlative analysis between receptor collective motions and binding energetics revealed that IMPHY000027 stabilized low‐energy conformational ensembles partially overlapping with those sampled by Pemafibrate (PPARα) and Pioglitazone (PPARγ). In contrast, IMPHY015538 populated distinct ligand‐dependent conformational states with comparatively weaker energetic coupling. Complementary density functional theory calculations highlighted differences in frontier‐orbital distributions and electronic features between the prioritized phytochemicals. In silico toxicity, target‐prediction, and pharmacokinetic analyses predicted for CNS compatibility and manageable off‐target profiles for both candidates. Collectively, these findings computationally prioritize IMPHY000027 as a putative dual PPARα/γ modulator exhibiting stable predicted receptor engagement and dynamic stability, providing a structure‐informed rationale for future experimental validation in models of radiation‐induced neuroinflammation and cognitive decline.