Targeting alternative holo-conformations of the gamma subtype of the proxisome proliferator activated receptor (PPARy) for the de novo in silico design of novel molecules with in vivo hypoglycaemic activity

Abstract

The thiazolidenedione class of drugs, represented by its flagship agonist molecule rosiglitazone has shown excellent potency and regulation of blood glucose levels in patients who did not respond to other oral hypoglycaemic agents. However, the PPARy agonist has also been associated with a number of undesirable effects that until recently has placed rosiglitazone at the centre of a controversy that debates whether or not this drug should be used clinically at all. Therefore it was on this premise that this de nova drug design project was based. Literature, and crystallographic evidence have shown different structural orientation of the PPARy Ligand Binding Pocket (PPARy_LBP) when it is bound to rosiglitazone (PDB deposition 1FM6), and when 1t 1s bound to its agonist counterpart fa1glitazar (PDB deposition 1FM9). Rosiglitazone and farglitazar are both full agonists and literature is indicative of the fact that the adverse effects could be related to the full agonistic effect of the ligands. In this respect, literature, has shown that partial agonists such as INTI 3 I (PDB deposition 3FUR) are free from the adverse effects of the full agonists. Rosiglitazone, farglitazar and INT13 I were chosen as templates for this de nova drug design study. Comparative binding affinity studies were carried out in order to gauge the affinity of rosiglitazone, farglitazar and INT13 I for their cognate and non-cognate LBP conformations.