PT  - JOURNAL ARTICLE
AU  - Omanakuttan, Athira
AU  - Nambiar, Jyotsna
AU  - Harris, Rodney M.
AU  - Bose, Chinchu
AU  - Pandurangan, Nanjan
AU  - Varghese, Rebu K.
AU  - Kumar, Geetha B.
AU  - Tainer, John A.
AU  - Banerji, Asoke
AU  - Perry, J. Jefferson P.
AU  - Nair, Bipin G.
TI  - Anacardic Acid Inhibits the Catalytic Activity of Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9
AID  - 10.1124/mol.112.079020
DP  - 2012 Oct 01
TA  - Molecular Pharmacology
PG  - 614--622
VI  - 82
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/82/4/614.short
4100  - http://molpharm.aspetjournals.org/content/82/4/614.full
SO  - Mol Pharmacol2012 Oct 01; 82
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 the effect of cashew nut shell extract (CNSE) on two matrix metalloproteinases, MMP-2/gelatinase A and MMP-9/gelatinase B, which 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 and MMP-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 the recombinant MMP-2 catalytic core domain demonstrated that anacardic acid directly inhibits substrate peptide cleavage in a dose-dependent manner, with an IC50 of 11.11 μM. In addition, our gelatinase zymography and fluorescence data confirmed that the cardol-cardanol mixture, salicylic acid, and aspirin, all of which lack key functional groups present in anacardic acid, are much weaker MMP-2/MMP-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.