Structural analysis of inhibition of Mycobacterium tuberculosis methionine aminopeptidase by bengamide derivatives

Jing Ping Lu, Xiu Hua Yuan, Qizhuang Ye

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Natural product-derived bengamides possess potent antiproliferative activity and target human methionine aminopeptidases for their cellular effects. Using bengamides as a template, several derivatives were designed and synthesized as inhibitors of methionine aminopeptidases of Mycobacterium tuberculosis, and initial antitubercular activity were observed. Here, we present three new X-ray structures of the tubercular enzyme MtMetAP1c in complex with the inhibitors in the Mn(II) form and in the Ni(II) form. All amide moieties of the bengamide derivatives bind to the unique shallow cavity and interact with a flat surface created by His-212 of MtMetAP1c in the Mn(II) form. However, the active site metal has significant influence on the binding mode, because the amide takes a different conformation in the Ni(II) form. The interactions of these inhibitors at the active site provide the structural basis for further modification of these bengamide inhibitors for improved potency and selectivity.

Original languageEnglish
Pages (from-to)479-484
Number of pages6
JournalEuropean Journal of Medicinal Chemistry
Volume47
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Aminopeptidases
Mycobacterium tuberculosis
Amides
Structural analysis
Methionine
Catalytic Domain
Derivatives
Biological Products
Human Activities
Conformations
Metals
X-Rays
X rays
Enzymes

Keywords

  • Antibiotic
  • Drug discovery
  • Metalloenzyme
  • Tuberculosis
  • X-ray structure

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Structural analysis of inhibition of Mycobacterium tuberculosis methionine aminopeptidase by bengamide derivatives. / Lu, Jing Ping; Yuan, Xiu Hua; Ye, Qizhuang.

In: European Journal of Medicinal Chemistry, Vol. 47, No. 1, 01.2012, p. 479-484.

Research output: Contribution to journalArticle

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