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Targeting the Akt1 allosteric site to identify novel scaffolds through virtual screening

Paper ID Volume ID Publish Year Pages File Format Full-Text
15136 1381 2014 13 PDF Available
Title
Targeting the Akt1 allosteric site to identify novel scaffolds through virtual screening
Abstract

•A first time virtual screening study targeting allosteric cavity of Akt1.•Both structure based and ligand based approaches were applied.•The interface between PH and kinase domains of Akt1 was targeted for inhibition.•Proposed molecules are potential leads for allosteric inhibition of Akt.

Preclinical data and tumor specimen studies report that AKT kinases are related to many human cancers. Therefore, identification and development of small molecule inhibitors targeting AKT and its signaling pathway can be therapeutic in treatment of cancer. Numerous studies report inhibitors that target the ATP-binding pocket in the kinase domains, but the similarity of this site, within the kinase family makes selectivity a major problem. The sequence identity amongst PH domains is significantly lower than that in kinase domains and developing more selective inhibitors is possible if PH domain is targeted. This in silico screening study is the first time report toward the identification of potential allosteric inhibitors expected to bind the cavity between kinase and PH domains of Akt1. Structural information of Akt1 was used to develop structure-based pharmacophore models comprising hydrophobic, acceptor, donor and ring features. The 3D structural information of previously identified allosteric Akt inhibitors obtained from literature was employed to develop a ligand-based pharmacophore model. Database was generated with drug like subset of ZINC and screening was performed based on 3D similarity to the selected pharmacophore hypotheses. Binding modes and affinities of the ligands were predicted by Glide software. Top scoring hits were further analyzed considering 2D similarity between the compounds, interactions with Akt1, fitness to pharmacophore models, ADME, druglikeness criteria and Induced-Fit docking. Using virtual screening methodologies, derivatives of 3-methyl-xanthine, quinoline-4-carboxamide and 2-[4-(cyclohexa-1,3-dien-1-yl)-1H-pyrazol-3-yl]phenol were proposed as potential leads for allosteric inhibition of Akt1.

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Keywords
Virtual screening; Molecular docking; Induced fit docking; Pharmacophore; Allosteric Akt inhibitor; Allosteric kinase inhibitor
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Targeting the Akt1 allosteric site to identify novel scaffolds through virtual screening
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Publisher
Database: Elsevier - ScienceDirect
Journal: Computational Biology and Chemistry - Volume 48, February 2014, Pages 1–13
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering
Get Full-Text Now
Don't Miss Today's Special Offer
Price was $35.95
You save - $31
Price after discount Only $4.95
100% Money Back Guarantee
Full-text PDF Download
Online Support
Any Questions? feel free to contact us