2g1q

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spinqualitylabelsall models 2g1q, resolution 2.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

crystal structure of KSP in complex with inhibitor 9h

Overview

Molecular modeling in combination with X-ray crystallographic information, was employed to identify a region of the kinesin spindle protein (KSP), binding site not fully utilized by our first generation inhibitors. We, discovered that by appending a propylamine substituent at the C5 carbon of, a dihydropyrazole core, we could effectively fill this unoccupied region, of space and engage in a hydrogen-bonding interaction with the enzyme, backbone. This change led to a second generation compound with increased, potency, a 400-fold enhancement in aqueous solubility at pH 4, and, improved dog pharmacokinetics relative to the first generation compound.

About this Structure

2G1Q is a Single protein structure of sequence from Homo sapiens with MG, ADP and N9H as ligands. Full crystallographic information is available from OCA.

Reference

Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP., Cox CD, Torrent M, Breslin MJ, Mariano BJ, Whitman DB, Coleman PJ, Buser CA, Walsh ES, Hamilton K, Schaber MD, Lobell RB, Tao W, South VJ, Kohl NE, Yan Y, Kuo LC, Prueksaritanont T, Slaughter DE, Li C, Mahan E, Lu B, Hartman GD, Bioorg Med Chem Lett. 2006 Jun 15;16(12):3175-9. Epub 2006 Apr 5. PMID:16603356

Page seeded by OCA on Mon Nov 12 22:13:05 2007