Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 3

Abstract

Alcohol dehydrogenase 3 (ADH3) has been assigned a role in nitric oxide homeostasis due to its function as an S-nitrosoglutathione reductase. As altered S-nitrosoglutathione levels are often associated with disease, compounds that modulate ADH3 activity might be of therapeutic interest. We performed a virtual screening with molecular dockings of more than 40,000 compounds into the active site of human ADH3. A novel knowledge-based scoring method was used to rank compounds, and several compounds that were not known to interact with ADH3 were tested in vitro. Two of these showed substrate activity (9-decen-1-ol and dodecyltetraglycol), where calculated binding scoring energies correlated well with the logarithm of the k (cat)/K (m) values for the substrates. Two compounds showed inhibition capacity (deoxycholic acid and doxorubicin), and with these data three different lines for specific inhibitors for ADH3 are suggested: fatty acids, glutathione analogs, and cholic acids.

QM/MM Calculations Revealing the Resting and Catalytic States in Zinc-Dependent Medium-Chain Dehydrogenases/Reductases

“…The input files were generated using the antechamber module in combination with the general amber force field (GAFF) . The amber force field parameters (force constants for bonds and angles) for nicotinamide cofactor NAD + were taken from the literature. , The hydrogen atoms were added by using the tleap module in Amber12, and the Amber99SB force field , for the protein was employed. The protein was surrounded by a 12 Å rectangular box of TIP3P water molecules .…”