title: Insights from selective non-phosphinic inhibitors of MMP-12 tailored to fit with an S1' loop canonical conformation.
abstract: After the disappointment of clinical trials with early broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs), the field is now resurging with a new focus on the development of selective inhibitors that fully discriminate between different members of the MMP family with several therapeutic applications in perspective. Here, we report a novel class of highly selective MMP-12 inhibitors, without a phosphinic zinc-binding group, designed to plunge deeper into the S(1)' cavity of the enzyme. The best inhibitor from this series, identified through a systematic chemical exploration, displays nanomolar potency toward MMP-12 and selectivity factors that range between 2 and 4 orders of magnitude toward a large set of MMPs. Comparison of the high resolution x-ray structures of MMP-12 in free state or bound to this new MMP-12 selective inhibitor reveals that this compound fits deeply within the S(1)' specificity cavity, maximizing surface/volume ratios, without perturbing the S(1)' loop conformation. This is in contrast with highly selective MMP-13 inhibitors that were shown to select a particular S(1)' loop conformation. The search for such compounds that fit precisely to preponderant S(1)' loop conformation of a particular MMP may prove to be an alternative effective strategy for developing selective inhibitors of MMPs.
authors.affiliation: Commissariat à l'Energie Atomique, Service d'Ingénierie Moléculaire de Protéines, CE-Saclay, 91191 Gif/Yvette Cedex, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Devel
authors.forename: Sandra
authors.initials: S
authors.lastname: Garcia
authors.forename: Bertrand
authors.initials: B
authors.lastname: Czarny
authors.forename: Fabrice
authors.initials: F
authors.lastname: Beau
authors.forename: Evelyne
authors.initials: E
authors.lastname: LaJeunesse
authors.forename: Laura
authors.initials: L
authors.lastname: Vera
authors.forename: Dimitris
authors.initials: D
authors.lastname: Georgiadis
authors.forename: Enrico
authors.initials: E
authors.lastname: Stura
authors.forename: Vincent
authors.initials: V
authors.lastname: Dive
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D057075:Enzyme Assays; D006801:Humans; D007700:Kinetics; D053508:Matrix Metalloproteinase 12 / Q000737:chemistry* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D010721:Phosphinic Acids / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D010721:Phosphinic Acids; D011480:Protease Inhibitors; D053508:Matrix Metalloproteinase 12
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