QUANTITATIVE MEASURES OF MOLECULAR SIMILARITY - METHODS TO ANALYZE TRANSITION-STATE ANALOGS FOR ENZYMATIC-REACTIONS

A formalism is presented for quantifying the similarity between any tw o molecules. The chemical descriptor used for comparison is the molecu lar electrostatic potential at the van der Waals surface. Thus, both t he spatial properties of a molecule and its chemical features are capt ured in this approach. For molecules that are geometrically alike, the most useful similarity measure stems from orienting the two species s o that their physical surfaces are aligned as well as possible, withou t regard to chemical patterns. After this alignment is achieved, a sin gle measure sensitive to the spatial distribution of the electrostatic potential is used to rank the electronic similarity. Molecular simila rity measures are applied to the enzyme systems AMP deaminase and AMP nucleosidase in order to understand quantitatively why their respectiv e transition-state inhibitors bind more tightly than do their substrat es. (C) 1996 John Wiley & Sons, Inc.