|
Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. January 2005, Volume 4, Number 1, 17-30 |
Theoretical Analysis of the Reactive Sites of Non-steroidal Anti-inflammatory Drugs
Nora Okulik and Alicia H. Jubert
Internet Electron. J. Mol. Des. 2005, 4, 17-30
|
Abstract:
Inflammation is a disease condition in which body tissues are
affected by heat, redness, swelling and pain. The therapeutic
effects of non-steroidal anti-inflammatory drugs (NSAIDs) are
well known regarding different diseases. Although there remain a
number of other potential sites of action for anti-inflammatory
agents, the mode of action of the NSAIDs is attributed primarily
to the inhibition of PG synthesis, and more specifically, to the
inhibition of the COX enzyme system. In an effort to gain a
deeper insight on the properties of NSAIDs as Indometacine,
{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic
acid}, Diclofenac, {[2-(2,6-dichlorophenyl) amino]-benzeneacetic
acid}, and Niflumic acids,
{2-3((3-trifluoromethyl)phenyl-amino)-3-pyridinecarboxylic acid}, that
will provide knowledge of their action and thus be potentially
helpful in the design of new drugs with therapeutic effects, we
have performed theoretical studies for the rationale design of
their activity mechanism. Further study of the NSAIDs
interaction with the receptor is being done. The conformational
space of these compounds has been scanned using molecular
dynamics in water and complemented with functional density
calculations. The Molecular Electrostatic Potential Maps (MEPs)
were obtained and analyzed and the corresponding topological
study was performed in the frame of the AIM Bader's theory
(atoms in molecules). The optimized geometries of Niflumic,
Diclofenac and Indometacine acids were used to carry out the
study of the topological properties of several Bond and Non
Bonding Critical Points as well as to analyze the Molecular
Electronic Potentials. Detailed information is reported herein or
deposited as supplementary material. The topological properties
of the NSAIDs studied show that the C-C, C-N and C-H ring
bonds are typical of covalent interactions. The C=O and O-H
bonds in the carboxylate groups are strong shared interactions.
Hydrogen bonds are only localized in the Niflumic acid. The
oxygen atoms of the carboxylic groups are sites of the highest
concentration of charge and it is assumed that these atoms shall
be the preferred sites for an electrophilic attack.
|