Virtual screening for ligands to human alcohol dehydrogenase 3

• Alcohol dehydrogenase 3 (ADH3) has been suggested a role in nitric oxide homeostasis due to its function as a S-nitrosoglutathione (GSNO) reductase. This has requested a modulator of the ADH3 activity for control of GSNO levels. Today virtual screenings are frequently used in drug discovery to dock and rank a large number of compounds. With molecular dockings of more than 40,000 compounds into the active site pocket of human ADH3 we ranked compounds with a novel method. Six top ranked compounds that were not known to interact with ADH3 were tested in vitro, where two showed substrate activity (9-decen-1-ol and dodecyltetraglycol), two showed inhibition capacity (deoxycholic acid and doxorubicin) and two did not have any detectable effect. For the substrates, site specific interactions and calculated binding scoring energies were determined with an extended docking simulation including flexible side chains of amino acids residues. The binding scoring energies correlated well with the logarithm of the substrates kcat over Km values. Furthermore, with these computational and experimental data three different lines for specific inhibitors for ADH3 are suggested: fatty acids, glutathione analogs and in addition deoxycholic acids.

Nyckelord

Alcohol dehydrogenase

Enzyme kinetics

Molecular docking

Virtual screening

NATURAL SCIENCES

NATURVETENSKAP

Publikations- och innehållstyp

vet (ämneskategori)

ovr (ämneskategori)