PT  - JOURNAL ARTICLE
AU  - Athira Omanakuttan
AU  - Jyotsna Nambiar
AU  - Rodney M Harris
AU  - Chinchu Bose
AU  - Nanjan Pandurangan
AU  - Rebu K Varghese
AU  - Geetha B Kumar
AU  - John A Tainer
AU  - Asoke Banerji
AU  - J.Jefferson P Perry
AU  - Bipin G Nair
TI  - Anacardic Acid Inhibits the Catalytic Activity of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9.
AID  - 10.1124/mol.112.079020
DP  - 2012 Jan 01
TA  - Molecular Pharmacology
PG  - mol.112.079020
4099  - http://molpharm.aspetjournals.org/content/early/2012/06/28/mol.112.079020.short
4100  - http://molpharm.aspetjournals.org/content/early/2012/06/28/mol.112.079020.full
AB  - Cashew Nut Shell Liquid (CNSL) has been used in traditional medicine for the treatment of a wide variety of pathophysiological conditions. To further define the mechanism of CNSL action, we investigated extracts of CNSL (CNSE) on two matrix metalloproteinases, MMP-2/Gelatinase-A and MMP-9/Gelatinase-B that are known to have critical roles in several disease states. We observed that the major constituent of CNSE, anacardic acid, markedly inhibited the gelatinase activity of 3T3-L1 cells. Our gelatin zymography studies on these two secreted gelatinases, present in the conditioned media from 3T3-L1 cells, established that anacardic acid directly inhibited the catalytic activities of both MMP-2/9. Our docking studies suggested that anacardic acid binds into the MMP-2/9 active site, with the carboxylate group of anacardic acid chelating the catalytic zinc ion, and forming a hydrogen bond to a key catalytic glutamate side chain, and the C15 aliphatic group being accommodated within the relatively large S1′ pocket of these gelatinases. In agreement with the docking results, our fluorescence-based studies on recombinant MMP-2 catalytic core domain demonstrated that anacardic acid directly inhibits substrate peptide cleavage in a dose-dependent manner, with an IC50 of 11.11μ M. Additionally, our gelatinase zymography and fluorescence data confirmed that cardol-cardanol mixture, salicylic acid and aspirin, all of which lack key functional groups present in anacardic acid, are much weaker MMP-2/-9 inhibitors. Our results provide the first evidence for inhibition of gelatinase catalytic activity by anacardic acid, providing a novel template for drug discovery and a molecular mechanism potentially involved in CNSL therapeutic action.