USE OF FLEXIBLE QUERIES FOR SEARCHING CONFORMATIONALLY FLEXIBLE MOLECULES IN DATABASES OF 3-DIMENSIONAL STRUCTURES

Searching for conformationally flexible molecules is currently a topic of widespread study. In general, this type of three-dimensional (3D) search can proceed by locating the flexibility information either in a database (by storing multiple conformers or conformational analysis results), or in a search engine (by implementing flexible fitting methods), or in a search query (by combining fixed and mobile query features). This paper describes the third approach, using a flexible pharmacophoric query for ACE inhibitors. 3D searches were performed using the MACCS-3D structural database system to search MDDR-3D, a database of about 17000 3D drug structures of current interest. The structures in the database were built using the CONCORD program. The paper describes a stepwise procedure for building the query, performing searches, and optimizing the query to obtain a high ratio of structures with the desired activity. The results offer a useful solution to the problem of searching conformationally flexible molecules in databases of 3D structures and illustrate how to introduce conformational flexibility in the domain of the search query.