Comparison of computer modelling and X-ray results of the binding of a pyrazole derivative to liver alcohol dehydrogenase.

The binding to liver alcohol dehydrogenase of the inhibitor 2,4-(4-pyrazolyl)-butylisothiourea has been studied both by modelling experiments using computer graphics with interactive energy minimization and by X-ray crystallographic structure determination. For the modelling experiments, we used the program system TOM, which was developed in our laboratory as an extension of the program FRODO. Different strategies for using computer graphics with interactive energy minimization were tested. Two essentially different binding modes were found. One of these was favoured from energy minimizations using a potential energy function which was the sum of a Coulomb interaction term and two different van der Waals' interaction terms for non-bonded and torsional interactions. This binding mode was close to the crystallographic observed structure. The results show that flexibility of both ligand and receptor side-chains as well as main-chain conformations are important for docking to the active site of liver alcohol dehydrogenase.