Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors

Jun Yong Choi, Rita Fuerst, Anna M. Knapinska, Alexander B. Taylor, Lyndsay Smith, Xiaohang Cao, P. John Hart, Gregg B. Fields, William R. Roush

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores of the chelating inhibitors (S)-10a, (R)-10a, and 10b were binding within the MMP-13 active site, the Zn2+ chelating unit was replaced with nonchelating polar residues that bridged over the Zn2+ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors 10d and (S)-17b, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn2+ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs.

Original languageEnglish (US)
Pages (from-to)5816-5825
Number of pages10
JournalJournal of Medicinal Chemistry
Volume60
Issue number13
DOIs
StatePublished - Jul 13 2017

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Matrix Metalloproteinase 13
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases
Binding Sites
Molecular Structure
Zinc
Catalytic Domain
Metals
X-Rays
Ions

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Choi, J. Y., Fuerst, R., Knapinska, A. M., Taylor, A. B., Smith, L., Cao, X., ... Roush, W. R. (2017). Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors. Journal of Medicinal Chemistry, 60(13), 5816-5825. https://doi.org/10.1021/acs.jmedchem.7b00514

Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors. / Choi, Jun Yong; Fuerst, Rita; Knapinska, Anna M.; Taylor, Alexander B.; Smith, Lyndsay; Cao, Xiaohang; Hart, P. John; Fields, Gregg B.; Roush, William R.

In: Journal of Medicinal Chemistry, Vol. 60, No. 13, 13.07.2017, p. 5816-5825.

Research output: Contribution to journalArticle

Choi, JY, Fuerst, R, Knapinska, AM, Taylor, AB, Smith, L, Cao, X, Hart, PJ, Fields, GB & Roush, WR 2017, 'Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors', Journal of Medicinal Chemistry, vol. 60, no. 13, pp. 5816-5825. https://doi.org/10.1021/acs.jmedchem.7b00514
Choi, Jun Yong ; Fuerst, Rita ; Knapinska, Anna M. ; Taylor, Alexander B. ; Smith, Lyndsay ; Cao, Xiaohang ; Hart, P. John ; Fields, Gregg B. ; Roush, William R. / Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors. In: Journal of Medicinal Chemistry. 2017 ; Vol. 60, No. 13. pp. 5816-5825.
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