title: Pharmacophore generation and atom-based 3D-QSAR of novel 2-(4-methylsulfonylphenyl)pyrimidines as COX-2 inhibitors.
abstract: Cyclooxygenase-2 (COX-2) inhibitors are widely used for the treatment of pain and inflammatory disorders such as rheumatoid arthritis and osteoarthritis. A series of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives has been reported as COX-2 inhibitors. In order to understand the structural requirement of these COX-2 inhibitors, a ligand-based pharmacophore and atom-based 3D-QSAR model have been developed. A five-point pharmacophore with four hydrogen bond acceptors (A) and one hydrogen bond donor (D) was obtained. The pharmacophore hypothesis yielded a 3D-QSAR model with good partial least-square (PLS) statistics results. The training set correlation is characterized by PLS factors (r (2) = 0.642, SD = 0.65, F = 82.7, P = 7.617 e - 12). The test set correlation is characterized by PLS factors (Q (2) (ext) = 0.841, RMSE = 0.24,Pearson-R = 0.91). A docking study revealed the binding orientations of these inhibitors at active site amino acid residues (Arg513, Val523, Phe518, Ser530, Tyr355, His90) of COX-2 enzyme. The results of ligand-based pharmacophore hypothesis and atom-based 3D-QSAR give detailed structural insights as well as highlights important binding features of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as COX-2 inhibitors which can provide guidance for the rational design of novel potent COX-2 inhibitors.
authors: Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune 411038, India.
authors: Ujashkumar A
authors: UA
authors: Shah
authors: Hemantkumar S
authors: HS
authors: Deokar
authors: Shivajirao S
authors: SS
authors: Kadam
authors: Vithal M
authors: VM
authors: Kulkarni
mesh_terms: D001665:Binding Sites; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016018:Least-Squares Analysis; D008024:Ligands; D008958:Models, Molecular; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D008024:Ligands; D011743:Pyrimidines; D051546:Cyclooxygenase 2; C030986:pyrimidine