title: Fragment-Based Discovery of 5-Arylisatin-Based Inhibitors of Matrix Metalloproteinases 2 and 13.
abstract: Matrix metalloproteinases (MMPs) are well-established targets for several pathologies. In particular, MMP-2 and MMP-13 play a prominent role in cancer progression. In this study, a structure-based screening campaign was applied to prioritize metalloproteinase-oriented fragments. This computational model was applied to a representative fragment set from the publically available EDASA Scientific compound library. These fragments were prioritized, and the top-ranking hits were tested in a biological assay to validate the model. Two scaffolds showed consistent activity in the assay, and the isatin-based compounds were the most interesting. These latter fragments have significant potential as tools for the design and realization of novel MMP inhibitors. In addition to their micromolar activity, the chemical synthesis affords flexible and creative access to their analogues.
authors.affiliation: Dipartimento di Farmacia, Università "G. d'Annunzio", Chieti, Via dei Vestini 31, 66013, Chieti, Italy. m.agamennone@unich.it.
authors.forename: Mariangela
authors.identifier: 0000-0001-5198-0051
authors.initials: M
authors.lastname: Agamennone
authors.affiliation: EDASA Scientific srls, Via Stingi 37, 66050, San Salvo, Italy.|Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia.
authors.forename: Dmitry S
authors.initials: DS
authors.lastname: Belov
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi "Aldo Moro" di Bari, Via Orabona 4, 70126, Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.affiliation: Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Ivanov
authors.affiliation: Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia.
authors.forename: Anton M
authors.initials: AM
authors.lastname: Novoselov
authors.affiliation: EDASA Scientific srls, Via Stingi 37, 66050, San Salvo, Italy.|Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia.
authors.forename: Ivan A
authors.initials: IA
authors.lastname: Andreev
authors.affiliation: Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia.
authors.forename: Nina K
authors.initials: NK
authors.lastname: Ratmanova
authors.affiliation: EDASA Scientific srls, Via Stingi 37, 66050, San Salvo, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Altieri
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi "Aldo Moro" di Bari, Via Orabona 4, 70126, Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortorella
authors.affiliation: Chemistry Department, Lomonosov Moscow State University, 119991, GSP-2, Leninskie gory, 1/3, Moscow, Russia. kurkin@direction.chem.msu.ru.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kurkin
mesh_terms: D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: 5-arylisatin; fragment-based screening; hit generation; inhibitors; matrix metalloproteinases