BIOMAT Database Logo BIOMAT Database Logo

Beta-diketo acid pharmacophore hypothesis. 1. Discovery of a novel class of HIV-1 integrase inhibitors. 2005

Raveendra Dayam, and Tino Sanchez, and Omoshile Clement, and Robert Shoemaker, and Shizuko Sei, and Nouri Neamati
Department of Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, California 90089, USA.

HIV-1 Integrase (IN) is an essential enzyme for viral replication. The discovery of beta-diketo acids was crucial in the validation of IN as a legitimate target in drug discovery against HIV infection. In this study, we discovered a novel class of IN inhibitors using a 3D pharmacophore guided database search. We used S-1360 (1), the first IN inhibitor to undergo clinical trials, and three other analogues to develop a common feature pharmacophore hypothesis. Testing this four-featured pharmacophore against a multiconformational database of 150,000 structurally diverse small molecules yielded 1,700 compounds that satisfied the 3D query. Subsequently, all 1,700 compounds were docked into the active site of IN. On the basis of docking scores, Lipinski's rule-of-five, and structural novelty, 110 compounds were selected for biological screening. We found that compounds that contain both salicylic acid and a 2-thioxo-4-thiazolidinone (rhodanine) group (e.g. 5-13) showed significant inhibitory potency against IN, while the presence of either salicylic acid or a rhodanine group alone did not. Although some of the compounds containing only a salicylic acid showed inhibitory potency against IN, none of the compounds containing only rhodanine exhibited considerable potency. Of the 52 compounds reported in this study, 11 compounds (5, 6, 8, 10-13, 32-33, 51, and 53) inhibited 3'-processing or strand transfer activities of IN with IC(50) < or = 25 microM. This is the first reported use of S-1360 and its analogues as leads in developing a pharmacophore hypothesis for IN inhibition and for identification of new compounds with potent inhibition of this enzyme.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D005663 Furans Compounds with a 5-membered ring of four carbons and an oxygen. They are aromatic heterocycles. The reduced form is tetrahydrofuran. Tetrahydrofurans
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D012236 Rhodanine
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013601 T-Lymphocytes Lymphocytes responsible for cell-mediated immunity. Two types have been identified - cytotoxic (T-LYMPHOCYTES, CYTOTOXIC) and helper T-lymphocytes (T-LYMPHOCYTES, HELPER-INDUCER). They are formed when lymphocytes circulate through the THYMUS GLAND and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T Cell,T Lymphocyte,T-Cells,Thymus-Dependent Lymphocytes,Cell, T,Cells, T,Lymphocyte, T,Lymphocyte, Thymus-Dependent,Lymphocytes, T,Lymphocytes, Thymus-Dependent,T Cells,T Lymphocytes,T-Cell,T-Lymphocyte,Thymus Dependent Lymphocytes,Thymus-Dependent Lymphocyte
D014230 Triazoles Heterocyclic compounds containing a five-membered ring with two carbon atoms and three nitrogen atoms with the molecular formula C2H3N3. Triazole
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs

Related Publications

Raveendra Dayam, and Tino Sanchez, and Omoshile Clement, and Robert Shoemaker, and Shizuko Sei, and Nouri Neamati
Design of novel bioisosteres of beta-diketo acid inhibitors of HIV-1 integrase.
January 2005, Antiviral chemistry & chemotherapy,
Raveendra Dayam, and Tino Sanchez, and Omoshile Clement, and Robert Shoemaker, and Shizuko Sei, and Nouri Neamati
Azido-containing aryl beta-diketo acid HIV-1 integrase inhibitors.
March 2003, Bioorganic & medicinal chemistry letters,
Raveendra Dayam, and Tino Sanchez, and Omoshile Clement, and Robert Shoemaker, and Shizuko Sei, and Nouri Neamati
A novel strategy to assemble the beta-diketo acid pharmacophore of HIV integrase inhibitors on purine nucleobase scaffolds.
October 2007, The Journal of organic chemistry,
Raveendra Dayam, and Tino Sanchez, and Omoshile Clement, and Robert Shoemaker, and Shizuko Sei, and Nouri Neamati
Design and synthesis of novel indole beta-diketo acid derivatives as HIV-1 integrase inhibitors.
October 2004, Journal of medicinal chemistry,
Raveendra Dayam, and Tino Sanchez, and Omoshile Clement, and Robert Shoemaker, and Shizuko Sei, and Nouri Neamati
Discovery of HIV-1 integrase inhibitors by pharmacophore searching.
March 1997, Journal of medicinal chemistry,
Raveendra Dayam, and Tino Sanchez, and Omoshile Clement, and Robert Shoemaker, and Shizuko Sei, and Nouri Neamati
Dihydroxythiophenes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore.
July 2006, Journal of virology,
Raveendra Dayam, and Tino Sanchez, and Omoshile Clement, and Robert Shoemaker, and Shizuko Sei, and Nouri Neamati
Novel quinolinonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, and biological activities.
August 2008, Journal of medicinal chemistry,
Raveendra Dayam, and Tino Sanchez, and Omoshile Clement, and Robert Shoemaker, and Shizuko Sei, and Nouri Neamati
HIV-1 integrase pharmacophore: discovery of inhibitors through three-dimensional database searching.
March 1997, Journal of medicinal chemistry,
Raveendra Dayam, and Tino Sanchez, and Omoshile Clement, and Robert Shoemaker, and Shizuko Sei, and Nouri Neamati
Design and synthesis of novel β-diketo derivatives as HIV-1 integrase inhibitors.
January 2012, Bioorganic & medicinal chemistry,
Raveendra Dayam, and Tino Sanchez, and Omoshile Clement, and Robert Shoemaker, and Shizuko Sei, and Nouri Neamati
Dynamic pharmacophore model optimization: identification of novel HIV-1 integrase inhibitors.
March 2006, Journal of medicinal chemistry,
Copied contents to your clipboard!