Ion specificity from COX to LOX, resulting in mono-oxygenated 15R-hydroxy-eicosatetraenoic acid (15R-HETE) production.302 On the other hand, the lowest productive dose of aspirin can permanently inhibit COX-1 and thereby suppress PG and TXA2 production as a promoter of platelet aggregation.33,34 Ibuprofen, ketoprofen, flurbiprofen, indomethacin, sulindac, and diclofenac are classical NSAIDs. They may be gradually reversible COX inhibitors and are applied broadly for antiinflammation therapy (Fig. 6).25 Ibuprofen can reversibly bind in the ASC of COX-1 and form a salt bridge of its carboxylic acid with Arg120. Indomethacin has been reported to be a time-dependent COX inhibitor that binds towards the hydrophobic pocket by the amino acids Ser530, Ala527, Val349, and Leu531. Notably, two chlorine atoms and also the carbonyl group of diclofenac are involved in numerous H-bonds with Ser530 and Tyr385 thatslightly enhance selectivity compared with that of other classical NSAIDs.35 Pyrazolidine-3,5-dione (oxicam) derivatives (e.g., piroxicam is an inhibitor of non-carboxylic acid function and consists of thiazine and carboxamide moieties) are non-selective COX-2 inhibitors except for meloxicam, which includes a slight inhibitory activity on COX-2 (see Fig. 5 and 7).36 The physicochemical properties of oxicams (keto nol tautomerism) are involved primarily in enzyme inhibition. Therefore, many H-bonds have already been observed in between thiazine and carboxamide moieties with Ser530, Tyr385, Arg120, and Tyr355 residues. Interestingly, oxicam binding within the ASC is accompanied by adjustments in protein conformation, which can be rare due to the fact classical NSAIDs undergo rotation of your Leu531 residue and have access to the side binding pocket.37 However, the newFig. 5 Relative COX-1/COX-2 selectivity of NSAIDs. IC50 1 = larger selectivity for COX-2, IC50 1 = greater selectivity for COX-1. ASA = aspirin. Reproduced from ref. 29 with permission from Dove Press Ltd, copyright 2021 ( 6 Chemical structure of the slightly selective and reversible COX inhibitors containing carboxylic acid.This journal would be the Royal Society of ChemistryRSC Med.Orexin A site Chem.Plumbagin MedChemExpress , 2022, 13, 47196 |ReviewRSC Medicinal ChemistryFig.PMID:23724934 7 Chemical structure of piroxicam and paracetamol as nonselective COX inhibitors devoid of a carboxylic acid functional group.Fig. 9 Chemical structure of SC-558.generation of COX-2 inhibitors lack a carboxylic-acid group, which leads to enzyme inhibition mostly via H-bond interactions with Ser530 and devoid of salt-bridge interactions with Arg120. Paracetamol is applied to treat discomfort and fever; it will not contain a carboxylic acid substructure and is linked with non-selective COX inhibition (Fig. 7).38,39 The precise mechanism of paracetamol action remains elusive as not too long ago reviewed by Przybyla et al.40 The uncommon pharmacological profile of this compound, i.e., the sturdy antipyretic activity paired using a weak anti-inflammatory activity, suggests a target beyond COX-1/2. Some information indicate that the inhibition of a COX-1 splice variant (COX-3) assumed to become expressed within the human pituitary gland as well as the hypothalamus could be relevant for the activity of paracetamol. However, the notion of COX-3 had to be rejected.23,41,42 The existing view assumes a mixed COX-1/2 inhibition within the central nervous program as a consequence of the lipophilicity of the drug. The diaryl heterocyclic coxibs (e.g., celecoxib, valdecoxib, rofecoxib, etoricoxib) have also been developed as selective COX-2 inhibi.