Rationalization of the inhibition activity of structurally related organometallic compounds against the drug target cathepsin B by DFT

A series of organometallic compds. of general formula [(arene)M(PTA)nXm]Y (arene = η6-C10H14, η-C5Me5); (M = Ru(II), Os(II), Rh(III) and Ir(III); X = Cl, mPTA; Y = OTf, PF6) have been screened for their cytotoxicity and ability to inhibit cathepsin B in vitro, in comparison to the antimetastatic compd. NAMI-A. The Ru and Os analogs and NAMI-A showed similar enzyme inhibition properties (with IC50 values in the low μM range), whereas the Rh(iii) and Ir(iii) compds. were inactive. To build up a rational for the obsd. differences, DFT calcns. 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 thermodn. in soln. Initial structure-activity relationships have been defined with the calcd. binding energies of the M-S bonds correlating well with the obsd. inhibition properties of the compds.