QSAR and conformational analysis of the antiinflammatory agent amfenac and analogues

TitleQSAR and conformational analysis of the antiinflammatory agent amfenac and analogues
Publication TypeJournal Article
Year of Publication1993
AuthorsRuiz, J, Lopez M, Mila J, Lozoya E, Lozano JJ, Pouplana R
JournalJournal of computer-aided molecular design
Pagination183 - 198
Date Published1993/04//
KeywordsAnti-Inflammatory Agents, Molecular; Molecular Conformation; Molecular Structure; Phenylacetates/chemistry; Structure-Activity Relationship, Non-Steroidal/chemistry; Models
AbstractThe new nonsteroidal antiinflammatory drug (NSAID) arylacetic amfenac (2-amino-3-benzoylphenylacetic acid) and 19 substituted derivatives were studied in order to correlate the biological activities with the structure-related parameters. The geometry of amfenac in neutral and anionic form was totally optimized, starting from standard geometries and crystallographic data, using semiempirical AM1 and MNDO quantum-mechanical methods. Conformational analysis shows the existence of a rigid structure for rotations of the acetic acid chain (alpha degrees) and the central carbonyl group (gamma degrees) around the bonds with the phenylamine ring, whereas the carboxyl group (beta degrees) and the phenyl ring of the benzoyl group (delta degrees) can rotate almost freely. Electrostatic potential maps were analyzed and showed that the electrostatic orientation effect seems to make an important contribution to the binding of the active compounds to prostaglandin synthase. An electrostatic orientation model of the binding site is proposed. The frontier orbital charge distribution was also described for each compound. On the other hand, steric, electronic and hydrophobic (log P) parameters were calculated and QSAR analysis showed that the most significant parameter for the antiinflammatory activity was the pi-electron density of the HOMO orbital in the second aromatic ring. These results suggest a possible electronic charge transfer between the aromatic fragments and the receptor.