title: Improving structure-based virtual screening by multivariate analysis of scoring data.
abstract: Three different multivariate statistical methods, PLS discriminant analysis, rule-based methods, and Bayesian classification, have been applied to multidimensional scoring data from four different target proteins: estrogen receptor alpha (ERalpha), matrix metalloprotease 3 (MMP3), factor Xa (fXa), and acetylcholine esterase (AChE). The purpose was to build classifiers able to discriminate between active and inactive compounds, given a structure-based virtual screen. Seven different scoring functions were used to generate the scoring matrices. The classifiers were compared to classical consensus scoring and single scoring functions. The classifiers show a superior performance, with rule-based methods being most effective. The precision of correctly predicting an active compound is about 90% for three of the targets and about 25% for acetylcholine esterase. On the basis of these results, a new two-stage approach is suggested for structure-based virtual screening where limited activity information is available.
authors.affiliation: Structural Chemistry, Biovitrum AB, SE-112 76 Stockholm, Sweden. micael.jacobsson@biovitrum.com
authors.forename: Micael
authors.initials: M
authors.lastname: Jacobsson
authors.forename: Per
authors.initials: P
authors.lastname: Lidén
authors.forename: Eva
authors.initials: E
authors.lastname: Stjernschantz
authors.forename: Henrik
authors.initials: H
authors.lastname: Boström
authors.forename: Ulf
authors.initials: U
authors.lastname: Norinder
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D001665:Binding Sites; D047628:Estrogen Receptor alpha; D015951:Factor Xa / Q000737:chemistry; D008024:Ligands; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry; D015999:Multivariate Analysis; D021281:Quantitative Structure-Activity Relationship; D011960:Receptors, Estrogen / Q000737:chemistry
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; D011960:Receptors, Estrogen; D000110:Acetylcholinesterase; D015951:Factor Xa; D019278:Matrix Metalloproteinase 3