title: Computational approaches to improve aggrecanase-1 inhibitory activity of (4-keto) phenoxy) methyl biphenyl-4-sulfonamide: group based QSAR and docking studies.
abstract: Group based Quantitative Structure Activity Relationship (GQSAR) was developed for thirty (4-keto-phenoxy) methyl biphenyl-4-sulfonamides which exhibit aggrecanase-1 enzyme inhibitory activity. This enzyme is involved in osteoarthritis. The data is divided into training and test sets, where the latter is used for validating the model. Substitution in the R(1) position plays a major role when compared to substitution in R(2) position. The former position is influenced by two descriptors, namely electrotopological and connectivity indices. R(2) position is influenced by radius of gyration. The statistical parameters for the training set (r(2) = 0.80, r(2)adj = 0.77, q(2) = 0.69, F-ratio = 26.80 and standard error = 0.24) and the predicted r(2) (r(2)(test) =0.95) are satisfactory. Docking of the compounds with aggrecanase-1 enzyme showed that there is a strong negative correlation between the binding energy and aggrecanase-1 inhibitory activity. Compounds with the carbonyl substitution interact with the S'1 pocket which is needed for enhanced activity. The two methodologies described here can help in lead optimization.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras, Adyar, Chennai-600036, India.
authors.forename: Ponnurengam Malliappan
authors.initials: PM
authors.lastname: Sivakumar
authors.forename: Naga Vignesh
authors.initials: NV
authors.lastname: Selvaraj
authors.forename: G
authors.initials: G
authors.lastname: Ramesh
authors.forename: J
authors.initials: J
authors.lastname: Mohanapriya
authors.forename: Veluchamy
authors.initials: V
authors.lastname: Prabhawathi
authors.forename: Mukesh
authors.initials: M
authors.lastname: Doble
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000071121:ADAMTS4 Protein; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors*; D021281:Quantitative Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*
chemical_list: D013449:Sulfonamides; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein