title: 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 S(2)' pocket of the enzyme with a set of nine alpha-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 S(2)' pocket and the second one the S(1) 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 r(2) of 0.500, respectively, were obtained. In conclusion, our data suggest a higher probability for the Phe(76) gated S(2)' open form pocket to accommodate the substituent alpha versus the wide solvent exposed S(1) subsite, probability which some research groups could have overlooked due to extensive use in their calculations of non revealing S(2)' pocket open state crystallographic structures instead of NMR ones.
authors.affiliation: Nicolae Simionescu Institute of Cellular Biology and Pathology 8, B.P. Haseu Street, Bucharest, 79691, Romania. istvan.svab@icbp.ro
authors.forename: I
authors.initials: I
authors.lastname: Svab
authors.forename: D
authors.initials: D
authors.lastname: Alexandru
authors.forename: Gabriella
authors.initials: G
authors.lastname: Vitos
authors.forename: Maria-Luiza
authors.initials: ML
authors.lastname: Flonta
mesh_terms: D000595:Amino Acid Sequence; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006860:Hydrogen Bonding; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009930:Organic Chemicals / Q000737:chemistry; D010649:Phenylalanine / Q000737:chemistry; D011485:Protein Binding; D013449:Sulfonamides / Q000037:antagonists & inhibitors*; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008024:Ligands; D009930:Organic Chemicals; D013449:Sulfonamides; D010649:Phenylalanine; D020778:Matrix Metalloproteinase 2