Homology modeling and ab initio calculations identify a basis for ligand selectivity for the PPARγ nuclear hormone receptor

The peroxisomal proliferation activator receptors (PPARs) are members of a superfamily of multidomain proteins known as the nuclear hormone receptors (NHRs), members of which have been shown to act as specific transcription factors. Other, perhaps better known examples of this family include the thyroid receptor, the various steroid receptors, vitamin D, and the retinoic acid receptors. It is only in the last few years that the target for a novel class of insulin‐sensitising drugs, the thiazolidine‐diones, was shown to be yet another member of this family, namely, the PPARγ receptor. These compounds have been shown to be clinically highly effective for the treatment of Type‐II diabetes. To help in the design of novel PPARγ agonists, the construction of a model of the receptor ligand binding domain was undertaken. A number of NHR structures have been published, but at the time this work commenced, no coordinates of these were available. Use was therefore made of the published stereopictures, to generate a 3D model of the trans ‐retinoic acid receptor, RARγ. From this, an homology model of the PPARγ receptor was generated. Docking of the natural prostaglandin ligand, 15‐deoxy‐Δ 12,14 ‐PGJ2, and a number of other PPARγ agonists, identified several potential binding pockets. The (energetically) best of these contained a key arginine which was unique to the PPARγ subtype and which, on the basis of ab initio molecular orbital calculations (6‐31G*), was shown, within the binding pocket, to selectively ionize the thiazolidinedione ring system. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 73: 97–111, 1999