title: Elaborate ligand-based pharmacophore exploration and QSAR analysis guide the synthesis of novel pyridinium-based potent beta-secretase inhibitory leads.
abstract: Beta-secretase (BACE) inhibitors have potential as anti-Alzheimer's disease treatments prompting us to explore the pharmacophoric space of 129 known BACE inhibitors. QSAR analysis was employed to select optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of explaining bioactivity variation (r(2)=0.88, F=60.48, r(LOO)(2)=0.85, r(PRESS)(2) against 25 external test inhibitors=0.71). We were obliged to use ligand efficiency as the response variable because the logarithmic transformation of bioactivities failed to access self-consistent QSAR models. Three pharmacophoric models emerged in the successful QSAR equation suggesting at least three binding modes accessible to ligands within BACE binding pocket. QSAR equation and pharmacophoric models were validated through ROC curves and were employed to guide synthesis of novel pyridinium-based BACE inhibitors. The best inhibitor illustrated an IC(50) value of 1.0 microM against BACE.
authors.affiliation: Department of Pharmaceutical Chemistry, Applied Science University, Amman, Jordan.
authors.forename: Afaf
authors.initials: A
authors.lastname: Al-Nadaf
authors.forename: Ghassan
authors.initials: G
authors.lastname: Abu Sheikha
authors.forename: Mutasem O
authors.initials: MO
authors.lastname: Taha
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D012372:ROC Curve
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011726:Pyridinium Compounds; D053829:Amyloid Precursor Protein Secretases