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 Chemjournal_title
European journal of medicinal chemistryauthors
Lu JP,Yuan XH,Ye QZdoi
10.1016/j.ejmech.2011.11.017subject
Has Abstractpub_date
2012-01-01 00:00:00pages
479-84issue
1eissn
0223-5234issn
1768-3254pii
S0223-5234(11)00839-7journal_volume
47pub_type
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