Quantitative structure-activity relationship studies of HIV-1 integrase inhibition. 1. GETAWAY descriptors.

The GEometry, Topology, and Atom-Weights AssemblY (GETAWAY) approach has been applied to the study of the HIV-1 integrase inhibition of 172 compounds that belong to 11 different chemistry families. A model able to describe more than 68.5% of the variance in the experimental activity was developed with the use of the mentioned approach. In contrast, none of the five different approaches, including the use of Randić Molecular Profiles, Geometrical, RDF, 3D-MORSE and WHIM descriptors was able to explain more than 62.4% of the variance in the mentioned property with the same number of variables in the equation. Finally, after extracting five compounds considered by us as outliers the model was able to describe more than 72.5% of the variance in the experimental activity.

[1]  A Wlodawer,et al.  Structure of the catalytic domain of avian sarcoma virus integrase with a bound HIV-1 integrase-targeted inhibitor. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Y. Pommier,et al.  Potent inhibitors of human immunodeficiency virus type 1 integrase: identification of a novel four-point pharmacophore and tetracyclines as novel inhibitors. , 1997, Molecular pharmacology.

[3]  F. Bushman,et al.  Identification of a small-molecule binding site at the dimer interface of the HIV integrase catalytic domain. , 2001, Acta crystallographica. Section D, Biological crystallography.

[4]  K. Kohn,et al.  Chicoric acid analogues as HIV-1 integrase inhibitors. , 1999, Journal of medicinal chemistry.

[5]  T R Burke,et al.  Salicylhydrazine-containing inhibitors of HIV-1 integrase: implication for a selective chelation in the integrase active site. , 1998, Journal of medicinal chemistry.

[6]  Mahindra T. Makhija,et al.  Molecular electrostatic potentials as input for the alignment of HIV-1 integrase inhibitors in 3D QSAR , 2001, J. Comput. Aided Mol. Des..

[7]  Mahindra T. Makhija,et al.  QSAR of HIV-1 integrase inhibitors by genetic function approximation method. , 2002, Bioorganic & medicinal chemistry.

[8]  H. Kubinyi.  Variable Selection in QSAR Studies. II. A Highly Efficient Combination of Systematic Search and Evolution , 1994 .

[9]  Aliuska Morales Helguera,et al.  TOPS-MODE based QSARs derived from heterogeneous series of compounds. Applications to the design of new anti-inflammatory compounds. , 2004, Bioorganic & medicinal chemistry.

[10]  Douglas D. Richman,et al.  HIV chemotherapy : AIDS , 2001 .

[11]  Alexander Golbraikh,et al.  Predictive QSAR modeling based on diversity sampling of experimental datasets for the training and test set selection , 2002, J. Comput. Aided Mol. Des..

[12]  Roberto Todeschini,et al.  Handbook of Molecular Descriptors , 2002 .

[13]  M. Teijeira,et al.  GETAWAY descriptors to predicting A(2A) adenosine receptors agonists. , 2005, European journal of medicinal chemistry.

[14]  D. A. Dougherty,et al.  Cation-π Interactions in Chemistry and Biology: A New View of Benzene, Phe, Tyr, and Trp , 1996, Science.

[15]  A. Tropsha,et al.  Beware of q2! , 2002, Journal of molecular graphics & modelling.

[16]  Y. Pommier,et al.  Coumarin-based inhibitors of HIV integrase. , 1997, Journal of medicinal chemistry.

[17]  Mahindra T. Makhija,et al.  Eigen Value Analysis of HIV-1 Integrase Inhibitors , 2001, J. Chem. Inf. Comput. Sci..

[18]  Y. Pommier,et al.  Thiazolothiazepine inhibitors of HIV-1 integrase. , 1999, Journal of medicinal chemistry.

[19]  Y. Pommier,et al.  Effects of tyrphostins, protein kinase inhibitors, on human immunodeficiency virus type 1 integrase. , 1995, Biochemistry.

[20]  R. Lipnick.  Outliers: their origin and use in the classification of molecular mechanisms of toxicity. , 1991, The Science of the total environment.

[21]  Cunxin Wang,et al.  Exploring binding mode for styrylquinoline HIV-1 integrase inhibitors using comparative molecular field analysis and docking studies. , 2004, Acta pharmacologica Sinica.

[22]  Maykel Pérez González,et al.  QSAR study of N6-(substituted-phenylcarbamoyl) adenosine-5′-uronamides as agonist for A1 adenosine receptors , 2004 .

[23]  M. Goldstein,et al.  Multivariate Analysis: Methods and Applications , 1984 .

[24]  Maykel Pérez González,et al.  A TOPS-MODE approach to predict adenosine kinase inhibition. , 2004, Bioorganic & medicinal chemistry letters.

[25]  Y. Pommier,et al.  Curcumin analogs with altered potencies against HIV-1 integrase as probes for biochemical mechanisms of drug action. , 1997, Journal of medicinal chemistry.

[26]  R. Dayam,et al.  Active site binding modes of the beta-diketoacids: a multi-active site approach in HIV-1 integrase inhibitor design. , 2004, Bioorganic & medicinal chemistry.

[27]  M Le Bret,et al.  Structure-activity relationships and binding mode of styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture. , 2000, Journal of medicinal chemistry.

[28]  G. Cohen,et al.  Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: a platform for antiviral drug design. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Y. Pommier,et al.  Arylamide inhibitors of HIV-1 integrase. , 1997, Journal of medicinal chemistry.

[30]  Mahindra T. Makhija,et al.  De novo design and synthesis of HIV-1 integrase inhibitors. , 2004, Bioorganic & medicinal chemistry.

[31]  Eamonn F. Healy,et al.  Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model , 1985 .

[32]  Mahindra T. Makhija,et al.  3D-QSAR and molecular modeling of HIV-1 integrase inhibitors , 2002, J. Comput. Aided Mol. Des..

[33]  R. Dayam,et al.  Synthesis of novel thiazolothiazepine based HIV-1 integrase inhibitors. , 2004, Bioorganic & medicinal chemistry.

[34]  Maykel Pérez González,et al.  TOPS-MODE Based QSARs Derived from Heterogeneous Series of Compounds. Applications to the Design of New Herbicides , 2003, J. Chem. Inf. Comput. Sci..

[35]  M C Nicklaus,et al.  HIV-1 integrase pharmacophore: discovery of inhibitors through three-dimensional database searching. , 1997, Journal of medicinal chemistry.

[36]  Maykel Pérez González,et al.  A topological substructural approach applied to the computational prediction of rodent carcinogenicity. , 2005, Bioorganic & medicinal chemistry.

[37]  M. Artico,et al.  2,6-Bis(3,4,5-trihydroxybenzylydene) derivatives of cyclohexanone: novel potent HIV-1 integrase inhibitors that prevent HIV-1 multiplication in cell-based assays. , 2004, Bioorganic & medicinal chemistry.

[38]  Douglas M. Hawkins,et al.  The Problem of Overfitting , 2004, J. Chem. Inf. Model..

[39]  Alexander Golbraikh,et al.  Rational selection of training and test sets for the development of validated QSAR models , 2003, J. Comput. Aided Mol. Des..

[40]  H. Akaike,et al.  Information Theory and an Extension of the Maximum Likelihood Principle , 1973 .

[41]  Hxugo Kubiny.  Variable Selection in QSAR Studies. I. An Evolutionary Algorithm , 1994 .

[42]  M C Nicklaus,et al.  Depsides and depsidones as inhibitors of HIV-1 integrase: discovery of novel inhibitors through 3D database searching. , 1997, Journal of medicinal chemistry.