title: Discovery of a new isomannide-based peptidomimetic synthetized by Ugi multicomponent reaction as human tissue kallikrein 1 inhibitor.
abstract: Human kallikrein 1 (KLK1) is the most extensively studied member of this family and plays a major role in inflammation processes. From Ugi multicomponent reactions, isomannide-based peptidomimetic 10 and 13 where synthesized and showed low micromolar values of IC50for KLK1 The most active compound (10) presented competitive mechanism, with three structural modifications important to interact with active site residues which corroborates its KLK1 inhibition. Finally, the most active compound also showed good ADMET profile, which indicates compound 10 as a potential hit in the search for new KLK1 inhibitors with low side effects.
authors.affiliation: Laboratório de Química Medicinal, Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, Rua Mario Viana 523, Santa Rosa, 24241-000 Niterói, RJ, Brazil.
authors.forename: Thalita G
authors.initials: TG
authors.lastname: Barros
authors.affiliation: Instituto Federal de Ciência, Tecnologia e Educação do Sul de Minas Gerais, Campus Inconfidentes, MG, Brazil.
authors.forename: Jorge A N
authors.initials: JAN
authors.lastname: Santos
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
authors.forename: Bruno E G
authors.initials: BEG
authors.lastname: de Souza
authors.affiliation: ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Ana Carolina R
authors.initials: ACR
authors.lastname: Sodero
authors.affiliation: ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Alessandra M T
authors.initials: AMT
authors.lastname: de Souza
authors.affiliation: ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Dayane P
authors.initials: DP
authors.lastname: da Silva
authors.affiliation: ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Carlos Rangel
authors.initials: CR
authors.lastname: Rodrigues
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Niterói, RJ, Brazil.
authors.forename: Sergio
authors.initials: S
authors.lastname: Pinheiro
authors.affiliation: Laboratório de Química Medicinal, Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, Rua Mario Viana 523, Santa Rosa, 24241-000 Niterói, RJ, Brazil.
authors.forename: Luiza R S
authors.initials: LRS
authors.lastname: Dias
authors.affiliation: ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Abrahim-Vieira
authors.affiliation: Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
authors.forename: Luciano
authors.initials: L
authors.lastname: Puzer
authors.affiliation: Laboratório de Química Medicinal, Departamento de Tecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal Fluminense, Rua Mario Viana 523, Santa Rosa, 24241-000 Niterói, RJ, Brazil. Electronic address: estelamuri@yahoo.com.br.
authors.forename: Estela M F
authors.initials: EMF
authors.lastname: Muri
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C502182:1,4-3,6-dianhydromannitol; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D057786:Peptidomimetics; C100936:KLK10 protein, human; D007610:Kallikreins
keywords: Inhibitors; Kallikreins; Molecular modeling; Peptidomimetics; Ugi reactions