Discovery of potential and selective COX-1 inhibitory leads using pharmacophore modelling, in silico screening and in vitro evaluation

•For the first time a pharmacophore of selective COX-1 inhibitors has been developed.•AHRR Pharmacophore model has been used as a 3D search query in SPECS database.•s-cis conformation of the amide bond favours fit into the COX-1 pharmacophore.•Hits displayed superior COX-1 inhibition and selectivity.•Clues for further designing of COX-1 selective inhibitors are discussed.

Cyclooxygenase −1 (COX-1) selective inhibitors are anticipated to be potential therapeutic agents for thrombosis, tumorigenesis, atherosclerosis, neuroprotection, and oxidative stress. In this study, a 3D-QSAR pharmacophore model was developed for potent and selective COX-1 inhibition based on 44 compounds from four different scaffolds using Phase, Schrödinger. One (hydrogen-bond) acceptor, one hydrophobic, and two aromatic sites (AHRR) contribute to COX-1 inhibitory activity. Test and decoy sets were used to corroborate the best hypothesis and the validated hypothesis was used to screen the SPECS database. The resultant hits were filtered by standard precision (SP) and extra precision (XP) modes of docking using Glide, Schrödinger which yielded five hits. Free energy calculations were carried out to quantify the affinity differences of the hits towards COX enzymes. These five hits were subjected to in vitro COX (ovine) inhibitory activity studies. The hits displayed potent COX-1 inhibitory activity and good selectivity versus COX-2 enzyme. The compounds also protected the nitric oxide (NO) induced cell death mediated by COX-1 in mouse macrophages cell line. Hence, we hypothesize that these compounds could be promising leads for the design of superior COX-1 inhibitors and insights gained from further exploration of the same could provide pertinent clues for the treatment of the conditions mentioned above.

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