7A16

CRYSTAL STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 IN COMPLEX WITH AN INHIBITOR GSK2229238A (COMPOUND 43)

Summary for 7A16

• Entry DOI: 10.2210/pdb7a16/pdb
• Descriptor: Methionine aminopeptidase 2, PHOSPHATE ION, 5,6-bis(fluoranyl)-3-(4-piperazin-1-yl-2-propan-2-yloxy-phenyl)-1~{H}-indole-2-carboxamide, ... (5 entities in total)
• Functional Keywords: methionine aminopeptidase-2, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 42699.26

Authors

Thorpe, J.H. (deposition date: 2020-08-11, release date: 2020-09-23, Last modification date: 2024-01-31)

Primary citation

Hirst, D.J.,Brandt, M.,Bruton, G.,Christodoulou, E.,Cutler, L.,Deeks, N.,Goodacre, J.D.,Jack, T.,Lindon, M.,Miah, A.,Page, K.,Parr, N.,Shukla, L.,Sims, M.,Thomas, P.,Thorpe, J.,Holmes, D.S.
Structure-based optimisation of orally active & reversible MetAP-2 inhibitors maintaining a tight 'molecular budget'.
Bioorg.Med.Chem.Lett., 30:127533-127533, 2020

PubMed Abstract: Structure-based led optimisation of orally active reversible Methionine Aminopeptidase-2 (MetAP-2) inhibitors utilising a 'molecular budget' medicinal chemistry strategy is described. The key physicochemical parameters of target molecules (cLogP, molecular size and H-bond donor count) were monitored through straightforward and intuitive use of atom count and distribution. The balance between structure-based design and an awareness of the physicochemical properties of the compounds synthesised enabled the rapid identification of a potent molecule with good oral pharmacokinetic (PK) characteristics by making fewer, higher quality compounds. The resulting candidate quality molecule was validated in a mechanistic cellular assay and a rodent secondary immunisation model.

PubMed: 32919012
DOI: 10.1016/j.bmcl.2020.127533

Experimental method

X-RAY DIFFRACTION (1.9 Å)