A Different Method for Steric Field Evaluation in CoMFA Improves Model Robustness

The all-grid probe Lennard-Jones 6−12 potential, typically used as steric descriptor in CoMFA, has been replaced by the volumes of van der Waals envelopes intersections between the probe-atom and the ligand molecules under investigation. The intersection volumes present a smoother distance dependence that overcomes the problems arising from formulation of a precise alignment and docking into the 3D lattice. A CoMFA-type application on a set of 78 steroid aromatase inhibitors with different grid and probe-atom characteristics suggests an improved model robustness for the new steric field in comparison with the classical 6−12 potential. Predefined cut-off and “minimum  sigma” values are not required. Systematic variation of the 3D lattice position leads to lower variations of cross-validated r-squared (q2LOO) at all levels of model complexity, which can be reduced with exclusion of some “interior” points. The relative simplicity and inexpensive computational demands make this steric field a promising altern...

[1]  E Di Salle,et al.  Novel aromatase and 5 alpha-reductase inhibitors. , 1994, The Journal of steroid biochemistry and molecular biology.

[2]  Tudor I. Oprea,et al.  Comparison of the Minimal Steric Difference (MTD) and Comparative Molecular Field Analysis (CoMFA) Methods for Analysis of Binding of Steroids to Carrier Proteins , 1993 .

[3]  Johann Gasteiger,et al.  Multivariate structure‐activity relationships between data from a battery of biological tests and an ensemble of structure descriptors: The PLS method , 1984 .

[4]  L S Hollis,et al.  cis-diamineplatinum (II) complexes containing phosphono carboxylate ligands as antitumor agents. , 1990, Journal of medicinal chemistry.

[5]  R. Brueggemeier,et al.  Steroidal inhibitors as chemical probes of the active site of aromatase , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[6]  Sorel Muresan,et al.  Van der Waals Intersection Envelope Volumes as a Possible Basis for Steric Interaction in CoMFA , 1996 .

[7]  James J. P. Stewart,et al.  MOPAC: A semiempirical molecular orbital program , 1990, J. Comput. Aided Mol. Des..

[8]  Matthew Clark,et al.  Comparative molecular field analysis (CoMFA). 2. Toward its use with 3D-structural databases , 1990 .

[9]  R. D'Alessio,et al.  4-aminoandrostenedione derivatives: A novel class of irreversible aromatase inhibitors. Comparison with FCE 24304 and 4-hydroxyandrostenedione , 1990, The Journal of Steroid Biochemistry and Molecular Biology.

[10]  R. Gillespie,et al.  2-(oxadiazolyl)- and 2-(thiazolyl)imidazo[1,2-a]pyrimidines as agonists and inverse agonists at benzodiazepine receptors. , 1991, Journal of medicinal chemistry.

[11]  N. Peet,et al.  Biological characterization of A-ring steroids , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[12]  Robert D Clark,et al.  Bioisosterism as a molecular diversity descriptor: steric fields of single "topomeric" conformers. , 1996, Journal of medicinal chemistry.

[13]  S. Wold,et al.  The Collinearity Problem in Linear Regression. The Partial Least Squares (PLS) Approach to Generalized Inverses , 1984 .

[14]  Romano T. Kroemer,et al.  Replacement of steric 6–12 potential-derived interaction energies by atom-based indicator variables in CoMFA leads to models of higher consistency , 1995, J. Comput. Aided Mol. Des..

[15]  Simon K. Kearsley,et al.  An alternative method for the alignment of molecular structures: Maximizing electrostatic and steric overlap , 1990 .

[16]  G. Klebe,et al.  Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. , 1994, Journal of medicinal chemistry.

[17]  G Klebe,et al.  On the prediction of binding properties of drug molecules by comparative molecular field analysis. , 1993, Journal of medicinal chemistry.

[18]  Robert D Clark,et al.  Neighborhood behavior: a useful concept for validation of "molecular diversity" descriptors. , 1996, Journal of medicinal chemistry.

[19]  S. Wold,et al.  Comparative molecular field analysis , 1991 .

[20]  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.

[21]  A Tropsha,et al.  Cross-validated R2-guided region selection for comparative molecular field analysis: a simple method to achieve consistent results. , 1995, Journal of medicinal chemistry.

[22]  Yvonne C. Martin.  Minimum Steric Difference. The MTD Method for QSAR Studies. , 1985 .

[23]  Glen Eugene Kellogg,et al.  HINT: A new method of empirical hydrophobic field calculation for CoMFA , 1991, J. Comput. Aided Mol. Des..

[24]  Jeremy G. Vinter,et al.  Extended electron distributions applied to the molecular mechanics of some intermolecular interactions , 1994, J. Comput. Aided Mol. Des..

[25]  A. Panzeri,et al.  Novel aromatase and 5α-reductase inhibitors , 1994, The Journal of Steroid Biochemistry and Molecular Biology.

[26]  Tudor I. Oprea,et al.  Three-dimensional quantitative structure-activity relationships of steroid aromatase inhibitors , 1996, J. Comput. Aided Mol. Des..

[27]  Ettore Novellino,et al.  Comparative Molecular Field Analysis on a Set of Muscarinic Agonists , 1991 .

[28]  D. E. Patterson,et al.  Crossvalidation, Bootstrapping, and Partial Least Squares Compared with Multiple Regression in Conventional QSAR Studies , 1988 .