title: Rationalization of the inhibition activity of structurally related organometallic compounds against the drug target cathepsin B by DFT.
abstract: A series of organometallic compounds of general formula [(arene)M(PTA)(n)X(m)]Y (arene = eta(6)-C(10)H(14), eta-C(5)Me(5)); M = Ru(ii), Os(ii), Rh(iii) and Ir(iii); X = Cl, mPTA; Y = OTf, PF(6)) have been screened for their cytotoxicity and ability to inhibit cathepsin B in vitro, in comparison to the antimetastatic compound NAMI-A. The Ru and Os analogues and NAMI-A showed similar enzyme inhibition properties (with IC(50) values in the low muM range), whereas the Rh(iii) and Ir(iii) compounds were inactive. In order to build up a rational for the observed differences, DFT calculations of the metal complexes adducts with N-acetyl-l-cysteine-N'-methylamide, a mimic for the Cys residue in the cathepsin B active site, were performed to provide insights into binding thermodynamics in solution. Initial structure-activity relationships have been defined with the calculated binding energies of the M-S bonds correlating well with the observed inhibition properties of the compounds.
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.forename: Fabio
authors.initials: F
authors.lastname: Edafe
authors.forename: Mikael
authors.initials: M
authors.lastname: Erlandsson
authors.forename: Luca
authors.initials: L
authors.lastname: Gonsalvi
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciancetta
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Re
authors.forename: Andrea
authors.initials: A
authors.lastname: Ienco
authors.forename: Luigi
authors.initials: L
authors.lastname: Messori
authors.forename: Maurizio
authors.initials: M
authors.lastname: Peruzzini
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000737:chemistry; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000633:toxicity; D018360:Crystallography, X-Ray; D004121:Dimethyl Sulfoxide / Q000031:analogs & derivatives / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008670:Metals / Q000737:chemistry; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000737:chemistry* / Q000633:toxicity; D017975:Ruthenium Compounds; D013329:Structure-Activity Relationship
chemical_list: D056831:Coordination Complexes; D008670:Metals; C520033:N-acetyl-L-cysteine-N-methylamide; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D002401:Cathepsin B; D000111:Acetylcysteine; D004121:Dimethyl Sulfoxide