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2D and 3D QSAR studies of diarylpyrimidine HIV-1 reverse transcriptase inhibitors. 2008

Joseph Rebehmed, and Florent Barbault, and Cátia Teixeira, and François Maurel
Université Paris Diderot (Paris 7), ITODYS (Interfaces, Traitements, Organisation et Dynamique des Systèmes), CNRS UMR 7086, Paris, France.

2D and 3D QSAR studies were applied on a set of 28 diarylpyrimidine derivatives to model and understand their HIV-1 reverse transcriptase (RT) inhibitory activities. Special cares were taken to build our set of molecules according to their bioactive conformations which is crucial to elaborate good QSAR models. 2D QSAR was performed using the heuristic method in CODESSA which had led to a linear model (R (2) = 0.928 and s (2) = 0.015) between the inhibitory activity and five descriptors. CoMFA and CoMSIA models were established using SYBYL package of programs. The better predictive ability of the CoMSIA model (q (2) = 0.730) over the CoMFA model (q (2) = 0.597) was assigned to the large contribution of hydrogen-bonding interactions to the inhibitory activity. CoMSIA physicochemical properties are in agreement with the 2D QSAR descriptors. The CoMSIA PLS contour surfaces were mapped to the binding pocket of the RT and showed that the results obtained by the 2D and 3D models are in respect with the protein environment. This link permitted us to validate our model and give important insights for the structure activity interpretations. These results will guide further structural modification and prediction of new HIV-1 RT inhibitors.

UI MeSH Term Description Entries
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D004268 DNA-Binding Proteins Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases. DNA Helix Destabilizing Proteins,DNA-Binding Protein,Single-Stranded DNA Binding Proteins,DNA Binding Protein,DNA Single-Stranded Binding Protein,SS DNA BP,Single-Stranded DNA-Binding Protein,Binding Protein, DNA,DNA Binding Proteins,DNA Single Stranded Binding Protein,DNA-Binding Protein, Single-Stranded,Protein, DNA-Binding,Single Stranded DNA Binding Protein,Single Stranded DNA Binding Proteins
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001426 Bacterial Proteins Proteins found in any species of bacterium. Bacterial Gene Products,Bacterial Gene Proteins,Gene Products, Bacterial,Bacterial Gene Product,Bacterial Gene Protein,Bacterial Protein,Gene Product, Bacterial,Gene Protein, Bacterial,Gene Proteins, Bacterial,Protein, Bacterial,Proteins, Bacterial
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D054303 HIV Reverse Transcriptase A reverse transcriptase encoded by the POL GENE of HIV. It is a heterodimer of 66 kDa and 51 kDa subunits that are derived from a common precursor protein. The heterodimer also includes an RNAse H activity (RIBONUCLEASE H, HUMAN IMMUNODEFICIENCY VIRUS) that plays an essential role the viral replication process. Reverse Transcriptase, HIV,Reverse Transcriptase, Human Immunodeficiency Virus,Transcriptase, HIV Reverse
D018894 Reverse Transcriptase Inhibitors Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. Reverse Transcriptase Inhibitor,Inhibitors, Reverse Transcriptase,Inhibitor, Reverse Transcriptase,Transcriptase Inhibitor, Reverse
D021281 Quantitative Structure-Activity Relationship A quantitative prediction of the biological, ecotoxicological or pharmaceutical activity of a molecule. It is based upon structure and activity information gathered from a series of similar compounds. Structure Activity Relationship, Quantitative,3D-QSAR,QSAR,QSPR Modeling,Quantitative Structure Property Relationship,3D QSAR,3D-QSARs,Modeling, QSPR,Quantitative Structure Activity Relationship,Quantitative Structure-Activity Relationships,Relationship, Quantitative Structure-Activity,Relationships, Quantitative Structure-Activity,Structure-Activity Relationship, Quantitative,Structure-Activity Relationships, Quantitative

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