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Potency and pharmacokinetics of broad spectrum and isoform-specific p110 gamma and delta inhibitors in cancers

Setti, Aravind and Kumar, Vijay MJ and Babu, Ravi K and Rasagna, A and Prasanna, Devi MGR and Devi, Phazna TA and Pawar, Smita C (2016) Potency and pharmacokinetics of broad spectrum and isoform-specific p110 gamma and delta inhibitors in cancers. In: JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION, 36 (1). pp. 26-36.

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Official URL: http://dx.doi.org/10.3109/10799893.2014.1003658

Abstract

Emerging data on cancer suggesting that target-based therapy is promising strategy in cancer treatment. PI3K-AKT pathway is extensively studied in many cancers; several inhibitors target this pathway in different levels. Recent finding on this pathway uncovered the therapeutic applications of PI3K-specific inhibitors; PI3K, AKT, and mTORC broad spectrum inhibitors. Noticeably, class I PI3K isoforms, p110 and p110 catalytic subunits have rational therapeutic application than other isoforms. Therefore, three classes of inhibitors: isoform-specific, dual-specific and broad spectrum were selected for molecular docking and dynamics. First, p110 structure was modelled; active site was analyzed. Then, molecular docking of each class of inhibitors were studied; the docked complexes were further used in 1.2ns molecular dynamics simulation to report the potency of each class of inhibitor. Remarkably, both the studies retained the similar kind of protein ligand interactions. GDC-0941, XL-147 (broad spectrum); TG100-115 (dual-specific); and AS-252424, PIK-294 (isoform-specific) were found to be potential inhibitors of p110 and p110, respectively. In addition to that pharmacokinetic properties are within recommended ranges. Finally, molecular phylogeny revealed that p110 and p110 are evolutionarily divergent; they probably need separate strategies for drug development.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the TAYLOR & FRANCIS LTD, 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND
Keywords: ADME; Glide; homology modeling; Molegro Virtual Docker; molecular dynamics; molecular docking; PI3K AKT pathway inhibitors; p110 delta structure
Department/Centre: Division of Biological Sciences > Biochemistry
Depositing User: Id for Latest eprints
Date Deposited: 04 Mar 2016 07:49
Last Modified: 04 Mar 2016 07:49
URI: http://eprints.iisc.ac.in/id/eprint/53319

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