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Molecular mechanics study of transannular amine–ketone (N→C(DOUBLE BOND)O) interaction in medium‐sized heterocycles
Author(s) -
Griffith R.,
Bremner J. B.,
Titmuss S. J.
Publication year - 1997
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/(sici)1096-987x(19970715)18:9<1211::aid-jcc9>3.0.co;2-u
Subject(s) - molecular mechanics , ketone , amine gas treating , computational chemistry , chemistry , double bond , organic chemistry , molecular dynamics
Medium‐sized nitrogen‐containing heterocycles have considerablepotential as structurally novel templates for new medicinal agents. Inorder to evaluate this potential and to investigate their binding tovarious target receptors, satisfactory modeling of the properties of suchcompounds with force‐field based computational methods is required,especially the conformations accessible to the molecules at and aroundtheir global minimum conformation. This is currently only possible withselected force fields for compounds that show a special intramolecularinteraction such as the transannular interaction between a basic nitrogenatom and a carbonyl carbon atom. This article substantiates this claim anddiscusses two approaches to modify the commercially available CFF91 forcefield. The different approaches are discussed and assessed by theirperformance in reproducing the conformation in the crystal for a series ofknown model compounds. In summary, very good agreement with theexperimental structure is achieved. The modified force fields are then usedto investigate a potentially bioactive lead compound. The lead compound ispredicted to be able to mimic the shape of a fused‐ring compound withbiological activity. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1211–1221