title: Isomannide derivatives as new class of inhibitors for human kallikrein 7.
abstract: Human kallikrein 7 (KLK7) is a potential target for the treatment of skin inflammation and cancer. Despite its potential, few KLK7-specific small-molecule inhibitors have been reported in the literature. As an extension of our program to design serine protease inhibitors, here we describe the in vitro assays and the investigation of the binding mechanism by molecular dynamics simulation of a novel class of pseudo-peptide inhibitors derived from isomannide. Of the inhibitors tested, two inhibited KLK7 with K(i) values in the low micromolar range (9g=1.8μM; 9j=3.0μM). Eadie-Hofstee and Dixon plots were used to evaluate the competitive mechanism of inhibition for the molecules. Calculated binding free energies using molecular MM/PB(GB)SA approach are in good agreement with experimental results, suggesting that the inhibitors share the same binding mode, which is stabilized by hydrophobic interactions and by a conserved network of hydrogen bonds. The promising results obtained in this study make these compounds valid leads for further optimization studies aiming to improve the potency of this new class of kallikrein inhibitors.
authors.affiliation: Instituto de Ciências Biológicas e Naturais, Universidade Federal do Triângulo Mineiro, Uberaba, MG, Brazil.
authors.forename: Renato F
authors.initials: RF
authors.lastname: Freitas
authors.forename: Thiago S P
authors.initials: TS
authors.lastname: Teixeira
authors.forename: Thalita G
authors.initials: TG
authors.lastname: Barros
authors.forename: Jorge A N
authors.initials: JA
authors.lastname: Santos
authors.forename: Marcia Y
authors.initials: MY
authors.lastname: Kondo
authors.forename: Maria A
authors.initials: MA
authors.lastname: Juliano
authors.forename: Luiz
authors.initials: L
authors.lastname: Juliano
authors.forename: Michael
authors.initials: M
authors.lastname: Blaber
authors.forename: Octávio A C
authors.initials: OA
authors.lastname: Antunes
authors.forename: Odonírio
authors.initials: O
authors.lastname: Abrahão
authors.forename: Sergio
authors.initials: S
authors.lastname: Pinheiro
authors.forename: Estela M F
authors.initials: EM
authors.lastname: Muri
authors.forename: Luciano
authors.initials: L
authors.lastname: Puzer
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: C502182:1,4-3,6-dianhydromannitol; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; C400147:KLK5 protein, human; C082472:KLK7 protein, human; D007610:Kallikreins