PDBsum entry 2g1q

Cell cycle

PDB id: 2g1q

Contents

Protein chains

330 a.a.

Ligands

ADP ×2

N9H ×2

Metals

_MG ×2

Waters ×169

References listed in PDB file

Key reference

• Title: 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.
• Authors: C.D.Cox, M.Torrent, M.J.Breslin, B.J.Mariano, D.B.Whitman, P.J.Coleman, C.A.Buser, E.S.Walsh, K.Hamilton, M.D.Schaber, R.B.Lobell, W.Tao, V.J.South, N.E.Kohl, Y.Yan, L.C.Kuo, T.Prueksaritanont, D.E.Slaughter, C.Li, E.Mahan, B.Lu, G.D.Hartman.
• Ref.: Bioorg Med Chem Lett, 2006, 16, 3175-3179. [DOI no: 10.1016/j.bmcl.2006.03.040]
• PubMed id: 16603356

Abstract

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.