ABSTRACT
Indoleamine 2,3-dioxygenase 1 (IDO1) is considered as a promising target for the treatment of several diseases, including neurological disorders and cancer. We report here the crystal structures of two IDO1/IDO1 inhibitor complexes, one of which shows that Amg-1 is directly bound to the heme iron of IDO1 with a clear induced fit. We also describe the identification and preliminary optimization of imidazothiazole derivatives as novel IDO1 inhibitors. Using our crystal structure information and structure-activity relationships (SAR) at the pocket-B of IDO1, we found a series of urea derivatives as potent IDO1 inhibitors and revealed that generation of an induced fit and the resulting interaction with Phe226 and Arg231 are essential for potent IDO1 inhibitory activity. The results of this study are very valuable for understanding the mechanism of IDO1 activation, which is very important for structure-based drug design (SBDD) to discover potent IDO1 inhibitors.
ABSTRACT
In our search for new PPARα/γ agonists, we designed and synthesized a series of benzoylazole-based carboxylic acids. Compound 9 showed potent PPARγ partial agonistic activity with modest PPARα agonistic activity. The sodium salt of 9 (9Na) demonstrated potent efficacy in lowering both blood glucose and lipids in an animal model without causing significant body weight gain, a well-known side effect associated with PPARγ full agonists.
Subject(s)
Azoles/chemical synthesis , Azoles/pharmacology , PPAR alpha/agonists , PPAR gamma/agonists , Animals , Azoles/chemistry , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , Mice , Models, Animal , Models, MolecularABSTRACT
Phosphodiesterase PDE12 is a medically important esterase-family member that hydrolyzes 2'-5'-linked oligoadenylates (2-5A), which are involved in the regulation of biological processes related to the antiviral and antitumour activity that can be induced by interferons. Here, cloning, purification and crystallization of the C-terminal endonuclease/exonuclease/phosphatase-homology domain of human PDE12 is reported. The crystals belonged to space group P3(1)21 or P3(2)21, with unit-cell parameters a = b = 111.3, c = 192.4 A, and diffracted to 2.5 A resolution. Assuming the presence of three molecules in the asymmetric unit, the solvent content was estimated to be about 44.0%.
Subject(s)
Phosphoric Diester Hydrolases/chemistry , Crystallization , Crystallography, X-Ray , HumansABSTRACT
Crystal structures of the catalytic domain of human stromelysin-1 (MMP-3) and collagenase-3 (MMP-13) with a hydroxamic acid inhibitor SM-25453 have been solved at 2.01 and 2.37A resolutions, respectively. The results revealed that the binding modes for this inhibitor to MMP-3 and -13 were quite similar. However, subtle comparative differences were observed at the bottom of S1' pockets, which were occupied with the guanidinomethyl moiety of the inhibitor. A remarkable feature of the inhibitor was the deep penetration of its long aliphatic chain into the S1' pocket and exposure of the guanidinomethyl moiety to the solvent.
