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

A series of organometallic compounds of general formula [(arene)M(PTA)nXm]Y (arene = eta6-C10H14, eta-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 compound NAMI-A. The Ru and Os analogues and NAMI-A showed similar enzyme inhibition properties (with IC50 values in the low mM 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.