Inhibition of MMP-1 and MMP-13 with phosphinic acids that exploit binding in the S2 pocket

Article abstract of DOI:10.1016/S0960-894X(98)00729-X

Through the use of empirical and computational methods, phosphinate- based inhibitors of MMP-1 and MMP-13 that bind into the S₂ pocket of these enzymes were designed. The synthesis and testing of 2 suggested that binding was occuring as hypothesized. Structure determination of a co-crystal of 2 bound to the catalytic domain of MMP-1 confirmed the binding mode. Substituents binding into S₂, S₁', S₂' and S₃', were optimized yielding compounds with low double-digit nM IC₅₀'s against these enzymes.