title: Evaluation of extended parameter sets for the 3D-QSAR technique MaP: implications for interpretability and model quality exemplified by antimalarially active naphthylisoquinoline alkaloids.
abstract: The 3D-QSAR technique MaP (Mapping Property distributions of molecular surfaces) characterises biologically active compounds in terms of the distribution of their surface properties (H-bond donor, H-bond acceptor, hydrophilic, weakly hydrophobic, strongly hydrophobic). The MaP descriptor is alignment-independent and yields chemically intuitive models. In this study, the impact of different operational parameters on the interpretability and model quality was investigated. Based on a set of antimalarially active naphthylisoquinoline alkaloids the effect of hydrophobicity assignment as well as the differentiation of H-bond propensity was evaluated according to a full factorial design. It turns out, that including different categories for H-bond donor strength significantly improved interpretability, reduced model complexity, and made possible the derivation of a novel pharmacophore hypothesis for this dataset. Further analysis of the factorial design reveals, that MaP models are robust to parameter changes and generate consistent models for different parameter settings.
authors.affiliation: Department of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Stiefl
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bringmann
authors.forename: Christian
authors.initials: C
authors.lastname: Rummey
authors.forename: Knut
authors.initials: K
authors.lastname: Baumann
mesh_terms: D000465:Algorithms; D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D021621:Imaging, Three-Dimensional; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D013499:Surface Properties
chemical_list: D000470:Alkaloids; D000962:Antimalarials; D007546:Isoquinolines; D009281:Naphthalenes