Quantitative measures of molecular similarity: Methods to analyze transition-state analogs for enzymatic reactions

A formalism is presented for quantifying the similarity between any two molecules. The chemical descriptor used for comparison is the molecular electrostatic potential at the van der Waals surface. Thus, both the spatial properties of a molecule and its chemical features are captured in this approach. For molecules that are geometrically alike, the most useful similarity measure stems from orienting the two species so that their physical surfaces are aligned as well as possible, without regard to chemical patterns. After this alignment is achieved, a single measure sensitive to the spatial distribution of the electrostatic potential is used to rank the electronic similarity. Molecular similarity measures are applied to the enzyme systems AMP deaminase and AMP nucleosidase in order to understand quantitatively why their respective transition-state inhibitors bind more tightly than do their substrates.