title: Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase.
abstract: Scientific disciplines such as medicinal- and environmental chemistry, pharmacology, and toxicology deal with the questions related to the effects small organic compounds exhort on biological targets and the compounds' physicochemical properties responsible for these effects. A common strategy in this endeavor is to establish structure-activity relationships (SARs). The aim of this work was to illustrate benefits of performing a statistical molecular design (SMD) and proper statistical analysis of the molecules' properties before SAR and quantitative structure-activity relationship (QSAR) analysis. Our SMD followed by synthesis yielded a set of inhibitors of the enzyme acetylcholinesterase (AChE) that had very few inherent dependencies between the substructures in the molecules. If such dependencies exist, they cause severe errors in SAR interpretation and predictions by QSAR-models, and leave a set of molecules less suitable for future decision-making. In our study, SAR- and QSAR models could show which molecular sub-structures and physicochemical features that were advantageous for the AChE inhibition. Finally, the QSAR model was used for the prediction of the inhibition of AChE by an external prediction set of molecules. The accuracy of these predictions was asserted by statistical significance tests and by comparisons to simple but relevant reference models.
authors.affiliation: Department of Chemistry, Umeå University, 90187, Umeå, Sweden.
authors.forename: C David
authors.initials: CD
authors.lastname: Andersson
authors.forename: J Mikael
authors.initials: JM
authors.lastname: Hillgren
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lindgren
authors.forename: Weixing
authors.initials: W
authors.lastname: Qian
authors.forename: Christine
authors.initials: C
authors.lastname: Akfur
authors.forename: Lotta
authors.initials: L
authors.lastname: Berg
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ekström
authors.forename: Anna
authors.initials: A
authors.lastname: Linusson
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism; D000704:Analysis of Variance; D060326:Chemistry Techniques, Synthetic; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015233:Models, Statistical; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase