title: Discovery of potent adenosine A2a antagonists as potential anti-Parkinson disease agents. Non-linear QSAR analyses integrated with pharmacophore modeling.
abstract: Adenosine A2A receptor antagonists are of great interest in the treatment for Parkinson's disease. In this study, we combined extensive pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis to explore the structural requirements for potent Adenosine A2A antagonists. Genetic function algorithm (GFA) joined with k nearest neighbor (kNN) analyses were applied to build predictive QSAR models. Successful pharmacophores were complemented with exclusion spheres to improve their receiver operating characteristic curve (ROC) profiles. Best QSAR models and their associated pharmacophore hypotheses were validated by identification of several novel Adenosine A2A antagonist leads retrieved from the National Cancer Institute (NCI) structural database. The most potent hit illustrated IC50 value of 545.7 nM.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan; Institut fuer Pharmazeutische and Medizinische Chemie, Heinrich-Heine-Universitaet Duesseldorf, 40225 Duesseldorf, Germany. Electronic address: m_khanfar@ju.edu.jo.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Khanfar
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan.
authors.forename: Saja
authors.initials: S
authors.lastname: Al-Qtaishat
authors.affiliation: Faculty of Pharmacy, Applied Sciences University, Amman, Jordan.
authors.forename: Maha
authors.initials: M
authors.lastname: Habash
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan. Electronic address: mutasem@ju.edu.jo.
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Taha
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D000465:Algorithms; D000978:Antiparkinson Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010300:Parkinson Disease / Q000188:drug therapy / Q000473:pathology; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D043705:Receptor, Adenosine A2A
keywords: Adenosine A(2A); Antagonists; Pharmacophore; QSAR