title: Discovery of a New Class of Potent MMP Inhibitors by Structure-Based Optimization of the Arylsulfonamide Scaffold.
abstract: A new class of potent matrix metalloproteinase (MMP) inhibitors designed by structure-based optimization of the well-known arylsulfonamide scaffold is presented. Molecules show an ethylene linker connecting the sulfonamide group with the P1' aromatic portion and a d-proline residue bearing the zinc-binding group. The affinity improvement provided by these modifications led us to discover a nanomolar MMP inhibitor bearing a carboxylate moiety as zinc-binding group, which might be a promising lead molecule. Notably, a significant selectivity for MMP-8, MMP-12, and MMP-13 was observed with respect to MMP-1 and MMP-7.
authors.affiliation: ProtEra Srl, Scientific Campus, University of Florence , viale delle idee 22, I-50019 Sesto Fiorentino, Italy ; Magnetic Resonance Center (CERM), University of Florence , via L. Sacconi 6, I-50019 Sesto Fiorentino, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Mori
authors.affiliation: ProtEra Srl, Scientific Campus, University of Florence , viale delle idee 22, I-50019 Sesto Fiorentino, Italy.
authors.forename: Assunta
authors.initials: A
authors.lastname: Massaro
authors.affiliation: Magnetic Resonance Center (CERM), University of Florence , via L. Sacconi 6, I-50019 Sesto Fiorentino, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Calderone
authors.affiliation: Magnetic Resonance Center (CERM), University of Florence , via L. Sacconi 6, I-50019 Sesto Fiorentino, Italy ; Department of Chemistry "Ugo Shiff", University of Florence , via della Lastruccia 3, I-50019 Sesto Fiorentino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Fragai
authors.affiliation: Magnetic Resonance Center (CERM), University of Florence , via L. Sacconi 6, I-50019 Sesto Fiorentino, Italy ; Department of Chemistry "Ugo Shiff", University of Florence , via della Lastruccia 3, I-50019 Sesto Fiorentino, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Luchinat
authors.affiliation: ICCOM-CNR , Dipartimento di Chimica "U. Schiff", via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mordini
keywords: MMP; X-ray; desolvation; docking; free energy; synthesis