title: The conformational landscape of tartrate-based inhibitors of the TACE enzyme as revealed by Hamiltonian Replica Exchange simulation.
abstract: The inhibitors of the Tumor Necrosis Factor-α Converting Enzyme represent promising tools for the treatment of Rheumatoid Arthritis, Multiple Sclerosis and other autoimmune diseases. In this work, using Hamiltonian Replica Exchange Molecular Dynamics simulations and atomistic force field we perform an accurate structural characterization of a group of tartrate-based inhibitors. The simulations highlight a correlation between the conformational landscape in bulk solvent and inhibition potency. Since the structures in bulk solvent are much more compact than the crystallographic bound state, we formulate the hypothesis of a two-step docking mechanism: (i) formation of an intermediate between the compact, hydroxyl exposing conformations in solution and the catalytic zinc ion; (ii) structural rearrangement in the active site of TACE of the zinc-tethered drug in the final binding conformation.
authors: Department of Chemistry, University of Florence, Florence, Italy.
authors: Carlo
authors: C
authors: Guardiani
authors: Piero
authors: P
authors: Procacci
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000072198:ADAM17 Protein; D020134:Catalytic Domain; D006801:Humans; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013237:Stereoisomerism; D013644:Tartrates / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D013644:Tartrates; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C029768:tartaric acid