5BWV

X-RAY CRYSTAL STRUCTURE AT 1.86A RESOLUTION OF HUMAN MITOCHONDRIAL BRANCHED CHAIN AMINOTRANSFERASE (BCATM) COMPLEXED WITH A PYRAZOLOPYRIMIDINONE COMPOUND AND AN INTERNAL ALDIMINE LINKED PLP COFACTOR.

Summary for 5BWV

• Entry DOI: 10.2210/pdb5bwv/pdb
• Related: 5BWR 5BWT 5BWU
• Descriptor: Branched-chain-amino-acid aminotransferase, mitochondrial, PYRIDOXAL-5'-PHOSPHATE, 2-[(4-chlorobenzyl)amino]-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile, ... (7 entities in total)
• Functional Keywords: fold type iv, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 85855.65

Authors

Somers, D.O. (deposition date: 2015-06-08, release date: 2015-07-01, Last modification date: 2019-06-12)

Primary citation

Bertrand, S.M.,Ancellin, N.,Beaufils, B.,Bingham, R.P.,Borthwick, J.A.,Boullay, A.B.,Boursier, E.,Carter, P.S.,Chung, C.W.,Churcher, I.,Dodic, N.,Fouchet, M.H.,Fournier, C.,Francis, P.L.,Gummer, L.A.,Herry, K.,Hobbs, A.,Hobbs, C.I.,Homes, P.,Jamieson, C.,Nicodeme, E.,Pickett, S.D.,Reid, I.H.,Simpson, G.L.,Sloan, L.A.,Smith, S.E.,Somers, D.O.,Spitzfaden, C.,Suckling, C.J.,Valko, K.,Washio, Y.,Young, R.J.
The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits.
J.Med.Chem., 58:7140-7163, 2015

PubMed Abstract: The hybridization of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm) based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimization of potency with maintenance of ligand efficiency, while the focus on physicochemical properties delivered compounds with excellent pharmacokinetic exposure that enabled a proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine, and valine in this acute study.

PubMed: 26090771
DOI: 10.1021/acs.jmedchem.5b00313

Experimental method

X-RAY DIFFRACTION (1.86 Å)