Exploring QSAR with E-state index: selectivity requirements for COX-2 versus COX-1 binding of terphenyl methyl sulfones and sulfonamides.
An attempt has been made to explore selectivity requirements for cyclooxygenase-2 (COX-2) versus cyclooxygenase-1 (COX-1) binding of terphenyl methyl sulfones and sulfonamides using electrotopological state (E-state) index and suitable indicator parameters. Multiple linear regression analyses produced statistically acceptable equations: the best relation based on 'all-possible-subsets regression' for COX-1 binding (n=18) showed predicted variance and explained variance of 0.675 and 0.777, respectively, while in case of the best equation for COX-2 binding (n=38), these values rose to 0.842 and 0.874, respectively. For the selectivity relation (n=17), predicted variance and explained variance values were 0.601 and 0.687, respectively. Based on the results of the analyses, three important sites have been suggested: sites A (methylsulfonyl or aminosulfonyl moiety), B (central phenyl ring), and C (terminal phenyl ring containing different substituents). All three sites are important for COX-2 binding while sites B and C are important for COX-1 binding. For COX-2 selectivity, only site C plays an important role. The study shows the utility of E-state index in developing statistically acceptable model having direct physicochemical significance.
Chakraborty
Santanu
S
Drug Theoretics and Cheminformatics Lab, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India.
Sengupta
Chandana
C
Roy
Kunal
K
D001665:Binding Sites; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry*; D004121:Dimethyl Sulfoxide; D004560:Electricity; D016014:Linear Models; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013450:Sulfones / Q000737:chemistry*; D013730:Terphenyl Compounds / Q000737:chemistry*
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D013449:Sulfonamides; D013450:Sulfones; D013730:Terphenyl Compounds; C025910:dimethyl sulfone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D004121:Dimethyl Sulfoxide