title: Discovery of potential and selective COX-1 inhibitory leads using pharmacophore modelling, in silico screening and in vitro evaluation.
abstract: 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.
authors.affiliation: Department of Pharmacology, PSG College of Pharmacy, Peelamedu, Coimbatore 641 004, Tamil Nadu, India.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Balaji
authors.affiliation: Department of Pharmaceutical Chemistry, PSG College of Pharmacy, Coimbatore 641 004, India.
authors.forename: Sivaram
authors.initials: S
authors.lastname: Hariharan
authors.affiliation: Department of Pharmacology, PSG College of Pharmacy, Peelamedu, Coimbatore 641 004, Tamil Nadu, India.
authors.forename: Darshit B
authors.initials: DB
authors.lastname: Shah
authors.affiliation: Department of Pharmacology, PSG College of Pharmacy, Peelamedu, Coimbatore 641 004, Tamil Nadu, India. Electronic address: muthiah.in@gmail.com.
authors.forename: Muthiah
authors.initials: M
authors.lastname: Ramanathan
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003198:Computer Simulation; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D015394:Molecular Structure; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D016861:Cyclooxygenase Inhibitors; D009569:Nitric Oxide; D051545:Cyclooxygenase 1
keywords: 3D QSAR; COX; Decoy; Docking; MM-GBSA; PHASE