The 4D-QSAR Paradigm: Application to a Novel Set of Non-peptidic HIV Protease Inhibitors

D-QSAR analysis incorporates pharmacophore, confor- mational and alignment freedom into the development of 3D-QSAR models for training sets of structure-activity data by performing ensemble averaging, the fourth ™di- mension∫. The data required to perform 4D-QSAR analysis includes a training set of compounds, usually analogs, and their measured biological activities in a common screen/assay. The 4D-QSAR approach can be applied to both receptor-dependent (RD) and receptor- independent (RI) problems. In the first scheme, the geometry of the receptor (molecular target, usually an enzyme) is available. In contrast, in the second scheme the geometry of the receptor is not part of the data available to perform the analysis. The descriptors in 4D-QSAR analysis are lattice grid cell (spatial) occupancy measures of atoms composing each molecule in the training set realized from the sampling of conformational and align- ment spaces. These grid cell occupancy descriptors (GCODs) are generated for a number of different atom types, the interaction pharmacophoric elements (IPEs). Non-GCOD descriptors can also be included with the set of GCODs in building the trial descriptor pool for model development. The idea underlying 4D-QSAR analysis is that the differences in activity among a set of ligands are related to differences in their Boltzmann average spatial distribution of molecular shape with respect to the IPEs. The 3D-QSAR models are generated and evaluated by a scheme that combines a genetic algorithm (GA) optimi- zation with partial least-squares (PLS) regression. A single ™active∫ conformation is postulated for each compound in the training set, which, when combined with the optimal alignment, can be used in additional molecular design applications, including other 3D-QSAR methods. The 4D- QSAR models can also be used as virtual screens in the processing of real and/or virtual ligand libraries. In this paper the 4D-QSAR paradigm is given in detail. More- over, we report the application of the (RI) 4D-QSAR formalism to a set of novel nonpeptidic HIV protease inhibitors. The 4D-QSAR models generated are robust and provide insight regarding the probable mechanism of action of the analogs, as well as hints concerning new synthetic routes. Furthermore, these models can be used as a starting point for future receptor-dependent anti-HIV drug design.

[1]  A. Warshel,et al.  Consistent Force Field for Calculations of Conformations, Vibrational Spectra, and Enthalpies of Cycloalkane and n‐Alkane Molecules , 1968 .

[2]  M. Dewar,et al.  Ground States of Molecules. 38. The MNDO Method. Approximations and Parameters , 1977 .

[3]  Anton J. Hopfinger,et al.  Application of Genetic Function Approximation to Quantitative Structure-Activity Relationships and Quantitative Structure-Property Relationships , 1994, J. Chem. Inf. Comput. Sci..

[4]  Norman L. Allinger,et al.  Conformational analysis. 130. MM2. A hydrocarbon force field utilizing V1 and V2 torsional terms , 1977 .

[5]  S. Hagen,et al.  Nonpeptide inhibitors of HIV protease , 2000 .

[6]  A. T. Hagler,et al.  Consistent force field studies of intermolecular forces in hydrogen-bonded crystals. 2. A benchmark for the objective comparison of alternative force fields , 1979 .

[7]  A. Leach.  Molecular Modelling: Principles and Applications , 1996 .

[8]  W J Dunn,et al.  A generalized formalism of three-dimensional quantitative structure-property relationship analysis for flexible molecules using tensor representation. , 1994, Journal of medicinal chemistry.

[9]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[10]  Anton J. Hopfinger,et al.  Four-Dimensional Quantitative Structure-Activity Relationship Analysis of a Series of Interphenylene 7-Oxabicycloheptane Oxazole Thromboxane A2 Receptor Antagonists , 1998, J. Chem. Inf. Comput. Sci..

[11]  Anton J. Hopfinger,et al.  A search for sources of drug resistance by the 4D-QSAR analysis of a set of antimalarial dihydrofolate reductase inhibitors , 2001, J. Comput. Aided Mol. Des..

[12]  David Rogers,et al.  G/SPLINES: A Hybrid of Friedman's Multivariate Adaptive Regression Splines (MARS) Algorithm with Holland's Genetic Algorithm , 1991, ICGA.

[13]  A. J. Hopfinger,et al.  Molecular mechanics force‐field parameterization procedures , 1984 .

[14]  A. Warshel,et al.  Consistent Force Field Calculations. II. Crystal Structures, Sublimation Energies, Molecular and Lattice Vibrations, Molecular Conformations, and Enthalpies of Alkanes , 1970 .

[15]  S. Lifson,et al.  Consistent force field studies of intermolecular forces in hydrogen-bonded crystals. 1. Carboxylic acids, amides, and the C:O.cntdot..cntdot..cntdot.H- hydrogen bonds , 1979 .

[16]  Anton J. Hopfinger,et al.  Prediction of Ligand-Receptor Binding Free Energy by 4D-QSAR Analysis: Application to a Set of Glucose Analogue Inhibitors of Glycogen Phosphorylase , 1999, J. Chem. Inf. Comput. Sci..

[17]  S E Hagen,et al.  4-Hydroxy-5,6-dihydropyrones as inhibitors of HIV protease: the effect of heterocyclic substituents at C-6 on antiviral potency and pharmacokinetic parameters. , 2001, Journal of medicinal chemistry.

[18]  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.

[19]  A. T. Hagler,et al.  Consistent force field studies of intermolecular forces in hydrogen-bonded crystals. 3. The C:O.cntdot..cntdot..cntdot.H-O hydrogen bond and the analysis of the energetics and packing of carboxylic acids , 1979 .

[20]  A. Hopfinger,et al.  Construction of 3D-QSAR Models Using the 4D-QSAR Analysis Formalism , 1997 .

[21]  Shen Wang,et al.  Construction of a Virtual High Throughput Screen by 4D-QSAR Analysis: Application to a Combinatorial Library of Glucose Inhibitors of Glycogen Phosphorylase b , 1999, J. Chem. Inf. Comput. Sci..

[22]  W. Dunn,et al.  Principal components analysis and partial least squares regression , 1989 .

[23]  Arnold T. Hagler,et al.  Urey-Bradley force field, valence force field, and ab initio study of intramolecular forces in tri-tert-butylmethane and isobutane , 1979 .

[24]  S. Lifson,et al.  Born–Oppenheimer energy surfaces of similar molecules: Interrelations between bond lengths, bond angles, and frequencies of normal vibrations in alkanes , 1982 .