Book of Abstracts: Albany 2009
June 16-20 2009
© Adenine Press (2008)
Pharmacophoric Analysis and Molecular Docking Studies on Selective Cyclooxygenase-2(COX-2) Inhibitors and Their Hits
The cellular targets or receptors of many drugs used for medical treatment are proteins. Drugs can either enhance or inhibit its activity by binding to the receptor. Basically there are two major groups of receptor proteins: (a) proteins that "float" around in the cytoplasm of the cell, (b) proteins that are incorporated into the cell membrane. In the latter case, a drug does not even need to enter the cell; it can bind simply to an extracellular binding site of the protein and control intracellular reactions from the outside. Specificity is an important criterion to determine the medical value of a drug. Drug has to bind specifically to the target protein in order to minimize undesired side-effects. On the molecular level specificity includes two more or less independent mechanisms, first the drug has to bind to its receptor site with a suitable affinity and second it has to either stimulate or inhibit certain movements of the receptor protein in order to regulate its activity. Both mechanisms are mediated by a variety of interactions between the drug and its receptor site.
In 1971, Vane showed that the anti-inflammatory action of nonsteroidal anti-inflammatory drugs (NSAIDs) rests in their ability to inhibit the activity of the cyclooxygenase (COX) enzyme, which in turn results in a diminished synthesis of proinflammatory prostaglandins (1). This action is considered to be not the sole but a major factor of the mode of action of NSAIDs. The pathway leading to the generation of prostaglandins has been elucidated. Within this process, the COX enzyme (also referred to as prostaglandin H synthase) catalyzes the first step of the synthesis of prostanoids by converting arachidonic acid into prostaglandin H2, which is the common substrate for specific prostaglandin synthases. The enzyme is bifunctional, with fatty acid COX activity (catalyzing the conversion of arachidonic acid to prostaglandin G2) and prostaglandin hydroperoxidase activity (catalyzing the conversion of prostaglandin G2 to prostaglandin H2). In the early 1990s, COX was demonstrated to exist as two distinct isoforms (2, 3). COX-1 is constitutively expressed as a housekeeping enzyme in nearly all tissues, and mediates physiological responses. Recent studies have further indicated that COX-2 over expression is not necessarily unique to cancer of the colon, but may be a common feature of other epithelial cells. Increased COX-2 levels have been identified in lung, breast, gastric, and prostate cancer, as well as in pancreatic adenocarcinomas (4). On the basis of these data, it is conceivable that specific COX-2 inhibitors might be used as adjuvant in the treatment of tumors, as well as in cancer prevention.
In this work we have find out common pharmacophoric feature required by COX-2 inhibitors to bind with receptor efficiently and then searched this common pharmacophore in Cambridge crystallographic database (CCDC) and performed molecular docking on hits and known inhibitors. we have also correlated the docking score and experimental data and suggested few refinement in existing COX-2 inhibitors.
Hydrogen bond interaction of SIKLIH and BANMUZ (compound searched from CCDC) within active site)
Our Pharmacophoric studies suggests that, there will be a specific arrangement of functional group required for molecule to work as COX-2 inhibitors, i.e., hydrophobic group, hydrogen bond acceptor, negative region, and aromatic rings in specific manner as mentioned in figure, our molecular docking study also supports this pharmacophoric requirement and shows very good interaction with the receptor for compounds with derived pharmacophore, hydrogen bond interaction shown in figure with unknown hits searched in CCDC database. So if we have these functional group according to the derived pharmacophoric features it enhances the activity of COX-2 inhibitors.
References and Footnotes
1Division of Toxicology