Premium
Probing the Peptidylglycine α‐Hydroxylating Monooxygenase Active Site with Novel 4‐Phenyl‐3‐butenoic Acid Based Inhibitors
Author(s) -
Langella Emma,
Pierre Sébastien,
Ghattas Wadih,
Giorgi Michel,
Réglier Marius,
Saviano Michele,
Esposito Luciana,
Hardré Renaud
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000214
Subject(s) - chemistry , substituent , stereochemistry , active site , in silico , monooxygenase , docking (animal) , enzyme , combinatorial chemistry , biochemistry , cytochrome p450 , medicine , nursing , gene
Specific inhibition of the copper‐containing peptidylglycine α‐hydroxylating monooxygenase (PHM), which catalyzes the post‐translational modification of peptides involved in carcinogenesis and tumor progression, constitutes a new approach for combating cancer. We carried out a structure–activity study of new compounds derived from a well‐known PHM substrate analogue, the olefinic compound 4‐phenyl‐3‐butenoic acid (PBA). We designed, synthesized, and tested various PBA derivatives both in vitro and in silico. We show that it is possible to increase PBA affinity for PHM by appropriate functionalization of its aromatic nucleus. Compound 2 d , for example, bears a meta ‐benzyloxy substituent, and exhibits better inhibition features ( K i =3.9 μ M , k inact / K i =427 M −1 s −1 ) than the parent PBA ( K i =19 μ M , k inact / K i =82 M −1 s −1 ). Docking calculations also suggest two different binding modes for PBA derivatives; these results will aid in the development of further PHM inhibitors with improved features.