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

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.

journal_name

Eur J Med Chem

authors

Lu JP,Yuan XH,Ye QZ

doi

10.1016/j.ejmech.2011.11.017

subject

Has Abstract

pub_date

2012-01-01 00:00:00

pages

479-84

issue

1

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(11)00839-7

journal_volume

47

pub_type

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