CHEMICAL FUNCTION QUERIES FOR 3D DATABASE SEARCH

The advent of three-dimensional (3D) molecular database searching motivates this investigation of how best to formulate queries for compounds likely to bind to an enzyme or receptor. 3D queries in the Literature generally refer to simple topological features (e.g., nitrogen or phenyl). To better capture the chemist's intent and to find functionally equivalent but structurally diverse compounds, generalized chemical function definitions are proposed for hydrogen bond accepters/donors, charge centers, and hydrophobes. Use of these function definitions in 5-HT3 antagonist and ACE inhibition queries is shown to identify dramatically more hits capable of forming the hypothesized interactions. Furthermore, false positives that have features inaccessible to the receptor are eliminated. Next, the literature on intermolecular interaction energy is reviewed to determine what geometric tolerances are chemically reasonable in queries. Finally, it is shown that the commonly used distance constraints poorly distinguish conformers that do and do not superimpose well with receptor features. An alternative, the location constraint, is proposed. Queries for angiotensin II antagonism and HLE inhibition are described and used to search 203 000 compounds.