Binding affinities for sulfonamide inhibitors with matrix metalloproteinase-2 using a linear response method

Abstract

Due to their involvement in many pathological conditions, matrix metalloproteinases (MMPs), are very attractive therapeutic targets. Our study focuses on one of them, MMP-2, which is involved in tumor progression and metastasis. Recently, the solution structure of the catalytic domain of MMP-2 complexed with a hydroxamic acid inhibitor (SC-74020) was published by Feng et al. Using the Hanessian group published binding affinity data and the structure published by Feng as a basis, we have built a binding affinity model by targeting the S2′ pocket of the enzyme with a set of nine α-N-sulfonylamino hydroxamic acid derivatives. Two binding geometries of each ligand have been generated corresponding to two binding modes denoted A and B, respectively, of which the first one is targeting the S2′ pocket and the second one the S1 pocket. For the binding affinity model developed for mode A the computed activities show a rmsd of 0.583 kcal/mol as compared with the experimental data, and a correlation coefficient r 2 of 0.779, while in the case of the binding mode B a rmsd of 0.834 kcal/mol and correlation coefficient r2 of 0.500, respectively, were obtained. In conclusion, our data suggest a higher probability for the Phe 76 gated S2′ open form pocket to accommodate the substituent α versus the wide solvent exposed S1 subsite, probability which some research groups could have overlooked due to extensive use in their calculations of non revealing S2′ pocket open state crystallographic structures instead of NMR ones.