title: Potent "clicked" MMP2 inhibitors: synthesis, molecular modeling and biological exploration.
abstract: A new series of MMP2 inhibitors is described, following a fragment-based drug design approach. One fragment containing an azide group and a well known hydroxamate Zinc Binding Group in a α-sulfone, α-tetrahydropyrane scaffold, has been synthesized. Water-LOGSY, STD and competition-STD experiments indicate that this fragment binds to the active site of the enzyme. A click chemistry reaction was used to connect the azide to lipophilic alkynes selected to interact selectively with the S1' subunit of MMP2, as shown by docking and molecular dynamic experiments of the designed compounds. The most potent compounds 18 and 19 displayed an IC(50) of 1.4 and 0.3 nM against MMP2 respectively, and showed negligible activity towards MMP1 and MMP7, two metalloproteinases which have a shallow S1' subsite. Compound 18 also showed a promising selectivity profile against some antitarget metalloproteinases, such as MMP8, and considerably less activity against MMP14 (IC(50) = 65 nM), and MMP9 (IC(50) = 98 nM), other MMPs characterized by having a deep S1' pocket and, therefore, more similar to MMP2.
authors.affiliation: Departamento de Química, Facultad de Farmacia, Universidad San Pablo CEU, Urbanización Montepríncipe, 28668, Boadilla del Monte, Madrid, Spain.
authors.forename: Jose María
authors.initials: JM
authors.lastname: Zapico
authors.forename: Pilar
authors.initials: P
authors.lastname: Serra
authors.forename: Josune
authors.initials: J
authors.lastname: García-Sanmartín
authors.forename: Kamila
authors.initials: K
authors.lastname: Filipiak
authors.forename: Rodrigo J
authors.initials: RJ
authors.lastname: Carbajo
authors.forename: Anne K
authors.initials: AK
authors.lastname: Schott
authors.forename: Antonio
authors.initials: A
authors.lastname: Pineda-Lucena
authors.forename: Alfredo
authors.initials: A
authors.lastname: Martínez
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Martín-Santamaría
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Pascual-Teresa
authors.forename: Ana
authors.initials: A
authors.lastname: Ramos
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001386:Azides / Q000737:chemistry; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical; D057930:Click Chemistry; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013450:Sulfones / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D001386:Azides; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013450:Sulfones; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1