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Purine-scaffold Hsp90 inhibitors.

ABSTRACT: Hsp90 is a molecular chaperone with important roles in regulating the function of several proteins with potential pathogenic activity. Because many of these proteins are involved in cancer and neurodegenerative promoting pathways, Hsp90 has emerged as an attractive therapeutic target in these diseases. Molecules that bind to the N-terminal nucleotide pocket of Hsp90 inhibit its activity, and consequently, disrupt client protein function. A number of these inhibitors from several chemical classes are now known, and some are already in clinical trials. This review focuses on the purine class of Hsp90 inhibitors, their discovery through rational design, and on efforts aimed towards their optimization and development into clinically viable drugs for the treatment of cancer. Their potential towards neurodegenerative diseases will also be touched upon.

SUBMITTER: Taldone T

PROVIDER: S-EPMC4699796 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Purine-scaffold Hsp90 inhibitors.

Taldone Tony T Chiosis Gabriela G

Current topics in medicinal chemistry 20090101 15

Hsp90 is a molecular chaperone with important roles in regulating the function of several proteins with potential pathogenic activity. Because many of these proteins are involved in cancer and neurodegenerative promoting pathways, Hsp90 has emerged as an attractive therapeutic target in these diseases. Molecules that bind to the N-terminal nucleotide pocket of Hsp90 inhibit its activity, and consequently, disrupt client protein function. A number of these inhibitors from several chemical classes ...[more]

PMID: 19860732

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The purine scaffold Hsp90 inhibitor PU-H71 sensitizes cancer cells to heavy ion radiation by inhibiting DNA repair by homologous recombination and non-homologous end joining.

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Prediction of new Hsp90 inhibitors based on 3,4-isoxazolediamide scaffold using QSAR study, molecular docking and molecular dynamic simulation.

Project description:BackgroundHeat shock protein90 (Hsp90) are overexpressed in tumor cells, so the inhibition of the Hsp90 ATPase activity would be a significantly effective strategy in cancer therapy.MethodsIn the current study, 3,4-isoxazolediamide derivatives were suggested as an Hsp90 inhibitor for anti-cancer therapy. Multiple linear regression (MLR) and genetic algorithm of partial least square (GA-PLS) methods were performed to build models to predict the inhibitory activity of Hsp90. The leave-one out (LOO) cross-validation and Y-randomization tests were performed to models' validation. The new ligands were monitored by applicability domain. Molecular docking studies were also conducted to evaluate the mode of interaction of these compounds with Hsp90. Identification of the likely pathways into the active site pocket and the involved residues were performed by CAVAER 3.0.1 software. According to QSAR models and docking analysis, three new compounds were predicted. 50 ns molecular dynamic simulation was performed for the strongest synthesized compound and the best predicted compound in terms of binding energy and interactions between ligand and protein.ResultsThe made models showed the significance of size, shape, symmetry, and branching of molecules in inhibitory activities of Hsp90. Docking studies indicated that two hydroxyl groups in the resorcinol ring were important in interacting with Asp93 and the orientation of these groups was related to substitution of different R1 groups. Comparing of molecular dynamic simulation (MDs) results shows that new compound perched in active site with lower binding energy than the best synthesized compound.ConclusionThe QSAR and docking analyses shown to be beneficial tools in the proposal of anti-cancer activities and a leader to the synthesis of new Hsp90 inhibitors based 3,4-isoxazolediamide. The MDs confirmed that predicted ligand is steady in the Hsp90 active sites.

| S-EPMC5493083 | biostudies-literature

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