Theoretical Analysis of the Reactive Sites of Nonsteroidal Antiinflammatory Drugs

N. B. OKULIK; A. H. JUBERT

Internet Electronic Journal of Molecular Design

BioChem Press

Lugar: Texas; Año: 2005 vol. 4 p. 17 - 30

1538-6414

Motivation. 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, Diclofenac and Niflumic acids 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. Method. 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). Results. 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. Conclusions. 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.