摘要：

Medium-sized nitrogen-containing heterocycles have considerable potential as structurally novel templates for new medicinal agents. In order to evaluate this potential and to investigate their binding to various target receptors, satisfactory modeling of the properties of such compounds with force-field based computational methods is required, especially the conformations accessible to the molecules at and around their global minimum conformation. This is currently only possible with selected force fields for compounds that show a special intramolecular interaction such as the transannular interaction between a basic nitrogen atom and a carbonyl carbon atom. This article substantiates this claim and discusses two approaches to modify the commercially available CFF91 force field. The different approaches are discussed and assessed 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 fields are then used to investigate a potentially bioactive lead compound. The lead compound is predicted to be able to mimic the shape of a fused-ring compound with biological activity. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1211–1221

展开