On the inhibition of alcohol dehydrogenase: Shape group analysis of molecular electrostatic potential on van der Waals surfaces for some pyrazole derivatives

Abstract

The assessment of molecular similarity between molecules is a fundamental task in computer-aided drug design. In this work, we have applied a combined analysis of steric and electrostatic properties of a series of inhibitors of liver alcohol dehydrogenase (LADH) to rationalize their action. The methodology is based on a topological characterization of the distribution of molecular electrostatic potential (MEP) on the fused-sphere van der Waals surface of a molecule. The topological description can be rendered in the form of two-dimensional diagrams that allow a quick visual or algorithmic analysis of the most relevant shape features of a molecule. By using the representations mentioned above (topological information as a function of the MEP), one can correlate this “structural” information with the values of inhibition constants KI for compounds with different levels of inhibitory activity. This approach allows one to have quantitative measures of similarity for related molecules and to eventually propose compounds that may exhibit a desired activity. The compounds analyzed in this work are a series of substituted derivatives of pyrazole, which span a relatively wide range of inhibitory powers. We have studied the role of the nature of the substituent, as well as its substitutional position, on the molecular shape and correlated these findings with the activity of each compound. Some consequences on the mechanism of inhibition of LADH are also discussed.