Media effects in modulating the conformational equilibrium of a model compound for tumor necrosis factor converting enzyme inhibition

•We studied the media effects on MBET306, a synthetic precursor for TACE inhibition.•We sampled the conformations of MBET306 in various solvent using REM simulations.•TD-DFT simulated spectra were obtained from conformational sampling.•Experimental excitation/emission spectra were interpreted using TD-DFT results.•Extended (TACE binding) structures of MBET306 are favored by amphiphatic solvents.

Small-molecule inhibitors of Tumor Necrosis Factor αα Converting Enzyme (TACE) are a promising therapeutic tool for Rheumatoid Arthritis, Multiple Sclerosis and other autoimmune diseases. Here we report on an extensive chemical–physical analysis of the media effects in modulating the conformational landscape of MBET306, the common scaffold and a synthetic precursor of a family of recently discovered tartrate-based TACE inhibitors. The structural features of this molecule with potential pharmaceutical applications have been disclosed by interpreting extensive photophysical measurements in various solvents with the aid of enhanced sampling molecular dynamics simulations and time dependent density functional calculations. Using a combination of experimental and computational techniques, the paper provides a general protocol for studying the structure in solution of molecular systems characterized by the existence of conformational metastable states.

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