title: 3D-QSAR CoMFA studies on bis-coumarine analogues as urease inhibitors: a strategic design in anti-urease agents.
abstract: A 3D-QSAR study has been performed on thirty (30) bis-coumarine derivatives to correlate their chemical structures with their observed urease inhibitory activity. Due to the absence of information on their active mechanism, comparative molecular field analysis (CoMFA) was used in the study. Two different properties: steric, electrostatic, assumed to cover the major contributions to ligand binding, were used to generate the 3D-QSAR model. Significant cross-validated correlation coefficients q(2) (0.558) and r(2) (0.992) for CoMFA were obtained, indicating the statistical significance of this class of compounds. The red electrostatic contour map highlighting those portion of compounds which may be interacting with nickel metal center in the active site of urease; while the blue contour map indicates positively charged groups in the ligands have improved biological activity and thus lower the IC(50)s. The steric contour map shows that bulkier substitutions at the 'R' position are detrimental to ligand receptor interaction. Actual urease inhibitory activities of this class and the predicted values were in good agreement with the experimental results. Moreover, from the contour maps, the key features vital to ligand binding have been identified, which are important for us to trace the important properties and gain insight into the potential mechanisms of intermolecular interactions between the ligand and receptor.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical Sciences, University of Karachi, Karachi-75270, Pakistan.
authors.lastname: Zaheer-ul-Haq
authors.forename: M Arif
authors.initials: MA
authors.lastname: Lodhi
authors.forename: Sarfraz
authors.initials: S
authors.lastname: Ahmad Nawaz
authors.forename: Sajid
authors.initials: S
authors.lastname: Iqbal
authors.forename: Khalid
authors.initials: K
authors.lastname: Mohammed Khan
authors.forename: Bernd M
authors.initials: BM
authors.lastname: Rode
authors.lastname: Atta-ur-Rahman
authors.forename: M Iqbal
authors.initials: MI
authors.lastname: Choudhary
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D005260:Female; D006801:Humans; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D014510:Urease / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D004791:Enzyme Inhibitors; D014510:Urease