Evaluation of extended parameter sets for the 3D-QSAR technique MaP: implications for interpretability and model quality exemplified by antimalarially active naphthylisoquinoline alkaloids.
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.
Stiefl
Nikolaus
N
Department of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Germany.
Bringmann
Gerhard
G
Rummey
Christian
C
Baumann
Knut
K
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
D000470:Alkaloids; D000962:Antimalarials; D007546:Isoquinolines; D009281:Naphthalenes