E-State Modeling of Corticosteroids Binding AffinityValidation of Model for Small Data Set

Data for 31 steroids binding to the corticosteroid binding globulin (CBG) were modeled using E-state molecular structure descriptors and a kappa shape index. Both E-state and hydrogen E-state descriptors appear in the model in atom-level and atom-type descriptors. A four-variable model is obtained that is statistically satisfactory: r (2) = 0.81, s = 0.51; r (2)(press) = 0.72; s(press) = 0.62. Structure interpretation is given for each variable in the model. A leave-group-out (LGO) approach to model-validation is presented in which each observation is removed from the data set three times in random groups of 20% of the whole data set. The average of the resulting predicted values constitutes consensus predictions for these data for which r (2)(LOO) = 0.70. These collective results support the claim that the E-state model may be useful for prediction of pK binding values for new compounds.

[1]  Eugene A. Coats,et al.  The CoMFA Steroids as a Benchmark Dataset for Development of 3D QSAR Methods , 1998 .

[2]  Lowell H. Hall,et al.  Modeling Antileukemic Activity of Carboquinones with Electrotopological State and Chi Indices , 1999, J. Chem. Inf. Comput. Sci..

[3]  P. McCluskey,et al.  Management of chronic uveitis , 2000, BMJ : British Medical Journal.

[4]  Jaroslaw Polanski,et al.  The Receptor-like Neural Network for Modeling Corticosteroid and Testosterone Binding Globulins , 1997, J. Chem. Inf. Comput. Sci..

[5]  Lemont B. Kier,et al.  Comparison of electrotopological state indexes with molecular orbital parameters : inhibition of MAO by hydrazides , 1993 .

[6]  L. Hall,et al.  The E-state in database analysis: the PCBs as an example , 1999 .

[7]  L B Kier,et al.  Molecular connectivity study of muscarinic receptor affinity of acetylcholine antagonists. , 1978, Journal of pharmaceutical sciences.

[8]  L B Kier,et al.  Molecular connectivity of phenols and their toxicity to fish , 1984, Bulletin of environmental contamination and toxicology.

[9]  Lemont B. Kier,et al.  E-state fields: Applications to 3D QSAR , 1996, J. Comput. Aided Mol. Des..

[10]  D. Rampton.  Regular review: Management of Crohn's disease , 1999 .

[11]  L B Kier,et al.  Structure-activity studies on hallucinogenic amphetamines using molecular connectivity. , 1977, Journal of medicinal chemistry.

[12]  Lemont B. Kier,et al.  QSAR modeling with the electrotopological state indices: Corticosteroids , 1998, Journal of computer-aided molecular design.

[13]  Lowell H. Hall,et al.  E-State Modeling of Dopamine Transporter Binding. Validation of the Model for a Small Data Set , 2000, J. Chem. Inf. Comput. Sci..

[14]  K. Mickelson,et al.  Steroid-protein interactions. Human corticosteroid binding globulin: some physicochemical properties and binding specificity. , 1981, Biochemistry.

[15]  O. Baud,et al.  Antenatal glucocorticoid treatment and cystic periventricular leukomalacia in very premature infants. , 1999, The New England journal of medicine.

[16]  A. Good,et al.  Structure-activity relationships from molecular similarity matrices. , 1993, Journal of medicinal chemistry.

[17]  H. Slavkin.  The body's skin frontier and the challenges of wound healing: keloids. , 2000, Journal of the American Dental Association.

[18]  Lowell H. Hall,et al.  Modeling the toxicity of amide herbicides using the electrotopological state , 1999 .

[19]  L B Kier,et al.  Molecular connectivity and substructure analysis. , 1978, Journal of pharmaceutical sciences.

[20]  Lemont B. Kier,et al.  Electrotopological State Indices for Atom Types: A Novel Combination of Electronic, Topological, and Valence State Information , 1995, J. Chem. Inf. Comput. Sci..

[21]  J. Gasteiger,et al.  Autocorrelation of Molecular Surface Properties for Modeling Corticosteroid Binding Globulin and Cytosolic Ah Receptor Activity by Neural Networks , 1995 .

[22]  R. Cramer,et al.  Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. , 1988, Journal of the American Chemical Society.

[23]  Shu-Shen Liu,et al.  QSAR Study of Steroid Benchmark and Dipeptides Based on MEDV-13 , 2001, J. Chem. Inf. Comput. Sci..