MOLECULAR MECHANICS STUDY OF TRANSANNULAR AMINE-KETONE (N-]C=O) INTERACTION IN MEDIUM-SIZED HETEROCYCLES

Medium-sized nitrogen-containing heterocycles have considerable potent ial as structurally novel templates for new medicinal agents. In order to evaluate this potential and to investigate their binding to variou s target receptors, satisfactory modeling of the properties of such co mpounds with force-field based computational methods is required, espe cially the conformations accessible to the molecules at and around the ir global minimum conformation. This is currently only possible with s elected force fields for compounds that show a special intramolecular interaction such as the transannular interaction between a basic nitro gen atom and a carbonyl carbon atom. This article substantiates this c laim and discusses two approaches to modify the commercially available CFF91 force field. The different approaches are discussed and assesse d by their performance in reproducing the conformation in the crystal for a series of known model compounds. In summary, very good agreement with the experimental structure is achieved. The modified force field s are then used to investigate a potentially bioactive lead compound. The lead compound is predicted to be able to mimic the shape of a fuse d-ring compound with biological activity. (C) 1997 by John Wiley & Son s, Inc.