Computational identification of potential chemoprophylactic agents according to dynamic behavior of peroxisome proliferator-activated receptor gamma.

Peroxisome proliferator-activated receptor gamma (PPAR γ ) is an attractive target for chemoprevention of lung carcinoma, however its highly dynamic nature has plagued drug development for decades, with difficulties in receptor modeling for structure-based design. In this work, an integrated receptor-based virtual screening (VS) strategy was applied to identify PPAR γ agonists as chemoprophylactic agents by using extensive docking and conformational sampling methods. Our results showed that the conformational plasticity of PPAR γ , especially the H2 & S245 loop, H2' & Ω loop and AF-2 surface, is markedly affected by binding of full/partial agonists. To fully take the dynamic behavior of PPAR γ into account, the VS approach effectively sorts out five commercial agents with reported antineoplastic properties. Among them, ZINC03775146 (gusperimus) and ZINC14087743 (miltefosine) might be novel PPAR γ agonists with the potential for chemoprophylaxis, that simultaneously take part in a flexible switch of the AF-2 surface and state change of the Ω loop. Furthermore, the dynamic structural coupling between the H2 & S245 and H2' & Ω loops offers enticing hope for PPAR γ -targeted therapeutics, by blocking kinase accessibility to PPAR γ . These results might aid the development of chemopreventive drugs, and the integrated VS strategy could be conducive to drug design for highly flexible biomacromolecules.