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)_nX_m]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 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.