Abstract
COX inhibitors which selectively inhibits the inducible COX-2 is an oenzyme that causes inflammation. They are clinically effective anti-inflammatory agents with less gastrointestinal and renal toxicity. However, they lack anti-thrombotic activity and hence lead to increased incidences of adverse cardiovascular trombotic events such as myocardial infarction. Therefore, there is still a need to develop better therapeutic effect and tolerability COX-2 inhibitor. The majority of COX-2 inhibitors are diaryl heterocycles. For optimum COX-2 selectivity and inhibitory potency a -SO(3)CH(3) or a- SO(2)NH(2) substituent at the para-position of phenyl ring was essential. A wide variety of heterocycles can serve as central ring system of the diaryl heterocycles structures. We report the screening of various 2,3-disubstituted-4(3H)-quinazolinones possessing benzenesulfonamide moiety, directly or indirectly bound to the ring system, using the Protein-Ligand ANT System (PLANTS) docking software against the COX-2 enzyme. Various molecular structures of ligands were docked and scored to identify structurally similar ligands to SC-558 (reference ligand) in binding interaction to COX-2 binding site. The results show that 2,3-disubstituted-4(3H)-quinazolinones possess pbenzenesulfonamide moiety at C-2, and phenyl moiety at N-3 binds directly or indirectly to the ring system with high binding affinity. The docked ligand has orientations similar to that observed with SC-558 satisfying Lipinski's rule of five.
Highlights
The Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are profoundly used in the treatment of a wide variety of inflammation conditions
The protein-ligand interaction score values obtained during docking, the docked poses obtained from visualization, and the properties of the ligands are given in Table 1
The crystal structure of COX-2 with SC-558 (S-58 in YASARA) reveals that the bromophenyl ring of SC-558 is bound in a hydrophobic cavity formed by Phe381, Tyr385, Trp387, Phe518, Met522, Val523, Ala527 and Ser530 and the trifluoromethyl group of the pyrazole ring binds in an adjacent pocket formed by Met113, Val116, Arg120, Val349, Tyr355, Leu359 dan Leu531
Summary
The Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are profoundly used in the treatment of a wide variety of inflammation conditions. They exhibit their effect by inhibiting cyclooxygenase (COX) activity. A single amino acid change, from the comparatively bulky isoleucine in COX-1 to valine at position 523 in COX-2, and the conformational changes it produces, resulted in enhanced access to a ‘side pocket’ that allowed the binding of COX-2 specific inhibitors by providing a docking site for bulky phenylsulfonamide residue of drugs such as SC-558 [5, 6]. The classical NSAIDs produce their adverse effects via inhibition of COX-1 isoform, many investigations have been directed to find compounds able to act as selective COX-2 inhibitors. The COX inhibitors such as celecoxib, valdecoxib and rofecoxib selectively inhibit COX-2 isoenzyme and clinically effective
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
