The Search for Cyclooxygenase-2 (COX-2) Inhibitors for the Treatment of Inflammation Disease: An in-silico Study

Abstract

Purpose Cyclooxygenase (COX-2) has been validated as a molecular target for treating inflammatory diseases. The present work was performed to identify potential COX-2 inhibitors by employing pharmacophore modeling. Methods The pharmacophore features consisted of seven features, ie, three hydrophobic, one negative ion, and three hydrogen bond acceptors, which were developed based on the structure of COX-2 inhibitor, (R)-naproxen. Results The pharmacophore model was validated with a Goodness of Hit (GH score) of 0.754 and the values of AUC100% 0.51. Screening against the ZINC database retrieved 1675 hits, while the molecular docking procedure identified four best hit molecules in term of binding orientation and binding energies, ie, Lig_1805/ZINC103584272 (E = −11.03 kcal/mol), Lig_553/ZINC408573132 (E = −10.92 kcal/mol), Lig_680/ZINC103584263 (E = −10.90 kcal/mol), and Lig_2006/ZINC19324645 (E = −10.62 kcal/mol). Conclusion The interactions of the four hits occurred in the binding site as (R)-naproxen did, and interestingly, their binding affinities were stronger than (R)-naproxen, implying their potential as COX-2 inhibitors.

Pharmacophore study, molecular docking and molecular dynamic simulation of virgin coconut oil derivatives as anti-inflammatory agent against COX-2

“…A set of bifunctional homodimeric enzymes, namely, COX-1 and COX-2 enzymes, catalysed arachidonic acid to produce prostaglandin (PG) H2 in the committed stage of PG biosynthesis [ 6 ]. Natural chemical derivatives from VCO can potentially inhibit and halt the pro-inflammatory signal expression by COX-2 with less side effects than classical NSAIDs (indomethacin aspirin, and ibuprofen) and inhibitors (celecoxib, rofecoxib, and valdecoxib) [ 5 , 22 ].…”

“…Further studies revealed in Table 2 showed that less hydrophobic interactions were exhibited by reference drugs compared to MCMs and MCFAs due to less flexibility of reference drugs present with aromatic group. The carboxyl moiety that provides HP, NI and HA pharmacophore features and interactions is a good inhibitor of COX-2 activity based on structure-based drug design [ 5 ]. On the other hand, despite salicylic acid and aspirin having carboxylate moiety does not participate in the binding of residues in active site which provides the explanation for the affinity of binding to COX-2 is not strong [ 6 ].…”

“…The natural response to infection or tissue injury is known as inflammation. It is normally restricted to the damaged tissues, but it can become uncontrolled in disorders such as asthma, nephritis, type-2 diabetes mellitus, malignancies and Alzheimer's disease if not dealt with appropriately [ 5 ]. Analgesics, such as narcotics and opioids, and nonsteroidal anti-inflammatory medications (NSAIDs), otherwise Ibuprofen and naproxen, are classically used to treat inflammation.…”

“…To search and create COX-based anti-inflammatory and anticancer medicines, several CADD or Computer Aided Drug Design methods have always been utilized. Virtual screening and docking-based technique were performed to find suitable COX-2 inhibitor [ 5 , 16 ]. On the other hand, Schaller et al (2020) used pharmacophore modelling combining ligand and structure-based models to screen out potential COX-2 inhibitor [ 5 , 17 ].…”

“…Virtual screening and docking-based technique were performed to find suitable COX-2 inhibitor [5,16]. On the other hand, Schaller et al (2020) used pharmacophore modelling combining ligand and structure-based models to screen out potential COX-2 inhibitor [5,17]. A few studies also reported in silico COX-2 inhibitory effect using the protein 5F1A included with molecular docking and molecular dynamics simulation [7,[18][19][20][21].…”