MMP2 and MMP9, also called gelatinases, play a primary role in the angiogenic switch, as a fundamental step of tumor progression, and show high degree of structural similarity. Clinically successful gelatinase inhibitors need to be highly selective as opposite effects have been found for the two enzymes, and the S1′ subsite is the major driver to attain selective and potent inhibitors. The synthesis of d-proline-derived hydroxamic acids containing diverse appendages at the amino group, varying in length and decoration allowed to give insight on the MMP2/MMP9 selectivity around the S1′ subsite, resulting in the identification of sub-nanomolar compounds with high selectivity up to 730. Molecular docking studies revealed the existence of an additional hydrophobic channel at the bottom of S1′ subsite for MMP2 enzyme useful to drive selectivity towards such gelatinase.
Identification of highly potent and selective MMP2 inhibitors addressing the S1′ subsite with d-proline-based compounds / E. Lenci, R. Innocenti, T. Di Francescantonio, G. Menchi, F. Bianchini, A. Contini, A. Trabocchi. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 27:9(2019 May 01), pp. 1891-1902.
|Titolo:||Identification of highly potent and selective MMP2 inhibitors addressing the S1′ subsite with d-proline-based compounds|
CONTINI, ALESSANDRO (Penultimo)
|Parole Chiave:||Peptidomimetics; Amino acids; Enzyme inhibition; Angiogenesis; Matrix metalloproteinase; Drug discovery; Docking|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Data di pubblicazione:||1-mag-2019|
|Data ahead of print / Data di stampa:||apr-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.bmc.2019.03.043|
|Appare nelle tipologie:||01 - Articolo su periodico|