Molecular insight into pemetrexed as a partial agonist of PPARγ through molecular dynamics simulations

Abstract

Pemetrexed (PMX), a first-line chemotherapeutic for non-small cell lung cancer (NSCLC), has recently been identified as a ligand of peroxisome proliferator-activated receptor gamma (PPAR_γ). However, the structural and dynamic basis of this interaction remains unclear. In this study, docking was combined with microsecond-scale molecular dynamics (MD) simulations to characterize PMX binding to the PPAR_γ ligand-binding domain (LBD). PMX was observed to adopt a binding pose resembling known partial agonists, stabilized by hydrogen bonds with residues Ser289, Tyr327, and Tyr473. Energetic and conformational analyses revealed that PMX avoids deep engagement with the AF-2 surface, which is a region critical for coactivator recruitment and full transcriptional activation. Free energy landscapes, principal component analysis, and dynamic cross-correlation maps further demonstrated that PMX induces conformational dynamics consistent with a partial agonist profile. This study provides an atomistic perspective on the recognition mechanism of PMX as a PPAR_γ partial agonist, offering a structural foundation for designing multitarget agents that simultaneously disrupt nucleotide metabolism and transcriptional regulation in NSCLC.