6ra1 | pdb_00006ra1
Human Cyclophilin D in complex with norbornane fragment derivative
Structural highlights
Function[PPIF_HUMAN] PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides. Involved in regulation of the mitochondrial permeability transition pore (mPTP). It is proposed that its association with the mPTP is masking a binding site for inhibiting inorganic phosphate (Pi) and promotes the open probablity of the mPTP leading to apoptosis or necrosis; the requirement of the PPIase activity for this function is debated. In cooperation with mitochondrial TP53 is involved in activating oxidative stress-induced necrosis. Involved in modulation of mitochondrial membrane F(1)F(0) ATP synthase activity and regulation of mitochondrial matrix adenine nucleotide levels. Has anti-apoptotic activity independently of mPTP and in cooperation with BCL2 inhibits cytochrome c-dependent apoptosis.[1] [2] Publication Abstract from PubMedFragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization. Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.,Gradler U, Schwarz D, Blaesse M, Leuthner B, Johnson TL, Bernard F, Jiang X, Marx A, Gilardone M, Lemoine H, Roche D, Jorand-Lebrun C Bioorg Med Chem Lett. 2019 Dec 1;29(23):126717. doi: 10.1016/j.bmcl.2019.126717. , Epub 2019 Oct 16. PMID:31635932[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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