Structure-Based Drug Design of a Novel Family of PPARγ Partial Agonists:  Virtual Screening, X-ray Crystallography, and in Vitro/in Vivo Biological Activities

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) is well-known as the receptor of thiazolidinedione antidiabetic drugs. In this paper, we present a successful example of employing structure-based virtual screening, a method that combines shape-based database search with a docking study and analogue search, to discover a novel family of PPARgamma agonists based upon pyrazol-5-ylbenzenesulfonamide. Two analogues in the family show high affinity for, and specificity to, PPARgamma and act as partial agonists. They also demonstrate glucose-lowering efficacy in vivo. A structural biology study reveals that they both adopt a distinct binding mode and have no H-bonding interactions with PPARgamma. The absence of H-bonding interaction with the protein provides an explanation why both function as partial agonists since most full agonists form conserved H-bonds with the activation function helix (AF-2 helix) which, in turn, enhances the recruitment of coactivators. Moreover, the structural biology and computer docking studies reveal the specificity of the compounds for PPARgamma could be due to the restricted access to the binding pocket of other PPAR subtypes, i.e., PPARalpha and PPARdelta, and steric hindrance upon the ligand binding.

The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands

“…In fact, it is a partial agonist of PPARc with a weaker transcriptional activity [52][53][54]. This relationship is in agreement with our previous findings regarding two enantiomeric ureidofibrate derivatives complexed with PPARc, showing partial and full agonism, respectively, toward this nuclear receptor [52].…”

“…9D). Interestingly, this compound makes no direct contacts with H12 residues, a hallmark of traditional TZDs, but preferentially stabilizes H3 through closer hydrophobic contacts or H-bonds made with residues of this helix (S289, F282, Q283 and Q286), likely affecting coactivator recruitment and transactivation potential [52][53][54]. Consistently, compound 2B may be considered a PPARc partial agonist and indeed displays a weaker transactivation profile than 2A (Fig.…”

Computational Methods in Drug Discovery

“…Compound 7 identified as a hit in the compound library screen. The binding mode of compound 7 obtained through docking study was used to define a core structure that was used for further similarity search which identified compound 1 as a potent agonist of PPAR-g. From Lu et al (2006). (Durrant et al, 2010b).…”

“…SB-vHTS has been used successfully in identifying novel and potent hits in several drug discovery campaigns Lu et al, 2006;Zhao et al, 2006;Ruiz et al, 2008;Triballeau et al, 2008;Li et al, 2009;Budzik et al, 2010;Izuhara et al, 2010;Simmons et al, 2010;Roughley et al, 2012). We discuss two examples in which SB-vHTS played pivotal role in discovery of lead compounds.…”

“…Discovery of Peroxisome Proliferator-Activated Receptor g Agonists. Lu et al (2006) successfully combined a docking study and analog search for designing agonists of peroxisome proliferator-activated receptor (PPAR) g, the receptor of thiazolidinedione antidiabetic drugs. A shape-based screening of the Maybridge data base using the shape of the bound conformation of a previously known agonist (PDB code 1K74) yielded 163 compounds.…”