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

Peroxisome proliferator-activated receptor gamma (PPAR) 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 agonists as chemoprophylactic agents by using extensive docking and conformational sampling methods. Our results showed that the conformational plasticity of PPAR, 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 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 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-targeted therapeutics, by blocking kinase accessibility to PPAR. These results might aid the development of chemopreventive drugs, and the integrated VS strategy could be conducive to drug design for highly flexible biomacromolecules.