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

A series of organometallic compounds of general formula [(arene)M(PTA) _nX_m]Y (arene = η⁶-C₁₀H ₁₄, 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 compound NAMI-A. The Ru and Os analogues and NAMI-A showed similar enzyme inhibition properties (with IC₅₀ values in the low μM 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.