Computational Characterization of tartrate-based TACE inhibitors

Small-molecule inhibitors of Tumor Necrosis factor alpha Converting Enzyme (TACE) are a promising therapeutic tool for Rheumatoid Arthritis, Multiple Sclerosis and other autoimmune diseases. Here we report on Hamiltonian Replica Exchange Molecular dynamics simulations of three tartrate-based TACE inhibitors. The simulations show that irrespective of the inhibition constant, the three drugs in bulk solvent adopt a common compact conformation whereby the hydrophobic right-hand side and left-hand side substituents are packed against each other and the hydroxyls necessary for Zinc chelation in the TACE active site are exposed toward the solvent. Since the drugs in complex with TACE are expected to be in the extended conformation, our results support the hypothesis of a structural rearrangement upon ligand binding. The proposed mechanism may have important implications for the rational drug design.