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Docking studies on isoform-specific inhibition of phosphoinositide-3-kinases.

ABSTRACT: Phosphatidylinositol 3-kinase ? (PI3K?) is a promising target for anticancer drug design. Oncogenic mutation H1047R in the catalytic domain is observed in many tumors and may enhance PI3K? kinase activity by affecting loop confirmations as well as membrane binding. We applied docking methods to 33 PI3K inhibitors against the wild type (wt) PI3K?, the H1047R mutant of PI3K? and the ? isoform of PI3K (PI3K?). We also investigated the effect of protein flexibility on ligand binding by docking the same set of ligands to conformations of the wt and mutant PI3K? generated by molecular dynamics simulations. Our data suggests that conformational differences in Gln859, Ser854, Tyr836, and Ser774 between the PI3K? wt and H1047R mutant may be used to design ligands that are active against both the wt and H1047R mutant isoforms. Gln859, Ser854 and Ser774 may play critical roles in ligand binding to the ? isoform H1047R mutant while formation of H-bonds with Ser806 of PI3K? may enhance ?-isoform-specific inhibition. In addition to H-bond interactions, structural and size differences in the activation and hydrophobic domains of PI3K?, PI3K?, and the PI3K? H1047R mutant could be exploited to direct the design of isoform- and/or mutant-specific PI3K inhibitors. Our data provide a reasonable explanation for the activity and selectivity of small molecular PI3K inhibitors and are in good agreement with available experimental and computational data.

SUBMITTER: Sabbah DA

PROVIDER: S-EPMC4480772 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Docking studies on isoform-specific inhibition of phosphoinositide-3-kinases.

Sabbah Dima A DA Vennerstrom Jonathan L JL Zhong Haizhen H

Journal of chemical information and modeling 20101001 10

Phosphatidylinositol 3-kinase α (PI3Kα) is a promising target for anticancer drug design. Oncogenic mutation H1047R in the catalytic domain is observed in many tumors and may enhance PI3Kα kinase activity by affecting loop confirmations as well as membrane binding. We applied docking methods to 33 PI3K inhibitors against the wild type (wt) PI3Kα, the H1047R mutant of PI3Kα and the γ isoform of PI3K (PI3Kγ). We also investigated the effect of protein flexibility on ligand binding by docking the s ...[more]

PMID: 20866085

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Project description:Sarcoidosis is a multisystem inflammatory disease characterized by the development of Th1/Th17/regulatory T cells (Tregs)-related non-caseating granulomas. Phosphoinositide-3 kinases δ/γ (PI3Kδ/γ) play an important role in the maintenance of effective immunity, especially for Tregs homeostasis and stability. In the present study, superoxide dismutase A (SodA) stimulation was used to establish the sarcoidosis mouse model. The second immune stimulus was accompanied by CAL-101 (PI3Kδ inhibitor) or AS-605240 (PI3Kδ/γ inhibitor) treatment. To detect the effect of the PI3Kδ/γ inhibitor on the morphology of pulmonary granuloma and the activation of the PI3K signaling pathway, hematoxylin and eosin staining and immunofluorescence and western blotting was used, respectively. Fluorescence-activated cell sorting analysis and reverse transcription-quantitative PCR were adopted to detect the effect of the PI3Kδ/γ inhibitor on the SodA-induced sarcoidosis mouse model in respect to immune cell disorder and the function of Treg cells, with CD4+CD25- T cells and CD4+CD25+ T cells sorted by magnetic cell sorting. The results demonstrated that the inhibition of PI3Kδ/γ by transtracheal CAL-101/AS-605240 administration facilitated pulmonary granuloma formation. These therapeutic effects were associated with certain mechanisms, including suppressing the aberrantly activated PI3K/Akt signaling in both pulmonary granuloma and Tregs, particularly rescuing the suppressive function of Tregs. Notably, CAL-101 was more effective in immune modulation compared with AS-605240 and could overcome the aberrantly activated Akt in the lung and Tregs. These results suggest that PI3K/Akt signaling, especially the PI3Kδ subunit, can play a key role in optimal Tregs-mediated protection against pulmonary sarcoidosis. Therefore, transtracheal usage of PI3Kδ/γ inhibitors is an attractive therapy that may be developed into a new immune-therapeutic principle for sarcoidosis in the future.

Dataset Information

Docking studies on isoform-specific inhibition of phosphoinositide-3-kinases.

Publications

Docking studies on isoform-specific inhibition of phosphoinositide-3-kinases.

Similar Datasets

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