title: 3D-QSAR Studies on Barbituric Acid Derivatives as Urease Inhibitors and the Effect of Charges on the Quality of a Model.
abstract: Urease enzyme (EC 3.5.1.5) has been determined as a virulence factor in pathogenic microorganisms that are accountable for the development of different diseases in humans and animals. In continuance of our earlier study on the helicobacter pylori urease inhibition by barbituric acid derivatives, 3D-QSAR (three dimensional quantitative structural activity relationship) advance studies were performed by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods. Different partial charges were calculated to examine their consequences on the predictive ability of the developed models. The finest developed model for CoMFA and CoMSIA were achieved by using MMFF94 charges. The developed CoMFA model gives significant results with cross-validation (q²) value of 0.597 and correlation coefficients (r²) of 0.897. Moreover, five different fields i.e., steric, electrostatic, and hydrophobic, H-bond acceptor and H-bond donors were used to produce a CoMSIA model, with q² and r² of 0.602 and 0.98, respectively. The generated models were further validated by using an external test set. Both models display good predictive power with r²pred ≥ 0.8. The analysis of obtained CoMFA and CoMSIA contour maps provided detailed insight for the promising modification of the barbituric acid derivatives with an enhanced biological activity.
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical &amp; Biological Sciences, University of Karachi, Karachi 75210, Pakistan. zaheer.qasmi@iccs.edu.
authors.forename: Zaheer
authors.initials: Z
authors.lastname: Ul-Haq
authors.affiliation: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical &amp; Biological Sciences, University of Karachi, Karachi 75210, Pakistan. sajda.ashraf@yahoo.com.
authors.forename: Sajda
authors.initials: S
authors.lastname: Ashraf
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. amajid@ksu.edu.sa.
authors.forename: Abdullah Mohammed
authors.initials: AM
authors.lastname: Al-Majid
authors.affiliation: Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. ambarakat@ksu.edu.sa.|Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426-Ibrahimia, Alexandria 21321, Egypt. ambarakat@ksu.edu.sa.
authors.forename: Assem
authors.initials: A
authors.lastname: Barakat
mesh_terms: D001463:Barbiturates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D030562:Databases, Protein; D016480:Helicobacter pylori / Q000201:enzymology; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D016018:Least-Squares Analysis; D062105:Molecular Docking Simulation; D025341:Principal Component Analysis; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D014510:Urease / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001463:Barbiturates; D014510:Urease; C032232:barbituric acid
keywords: 3D-QSAR; CoMFA; CoMSIA; barbituric acid derivatives; molecular docking; urease inhibitor