Homology modeling and ab initio calculations identify a basis for ligand selectivity for the PPAR gamma 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 f actors. Other, perhaps better known examples of this family include the thy roid receptor, the various steroid receptors, vitamin D, and the retinoic a cid receptors. It is only in the last few years that the target for a novel class of insulin-sensitising drugs, the thiazolidinediones, was shown to b e yet another member of this family, namely, the PPAR gamma receptor. These compounds have been shown to be clinically highly effective for the treatm ent of Type-II diabetes. To help in the design of novel PPAR gamma agonists , the construction of a model of the receptor ligand binding domain was und ertaken. A number of NHR structures have been published, but at the time th is work commenced, no coordinates of these were available. Use was therefor e made of the published stereopictures, to generate a 3D model of the trans -retinoic acid receptor, RAR gamma. From this, an homology model of the PPA R gamma receptor was generated. Docking of the natural prostaglandin ligand , 15-deoxy-Delta(12,14)-PGJ2, and a number of other PPAR gamma agonists, id entified several potential binding pockets. The (energetically) best of the se contained a key arginine which was unique to the PPAR gamma subtype and which, on the basis of ab initio molecular orbital calculations (6-31G*), w as shown, within the binding pocket, to selectively ionize the thiazolidine dione ring system. (C) 1999 John Wiley & Sons, Inc. Int J Quant Chem 73: 97 -111, 1999.