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Isoform-specific Role of Akt Kinase in Cancer and its Selective Targeting by Potential Anticancer Natural Agents

Author(s):

Nand Kishor Roy, Javadi Monisha, Anuj Singh, Ganesan Padmavathi and Ajaikumar B Kunnumakkara*  

Abstract:


Background: Akt kinase is a serine/threonine kinase that plays an important role in different cellular processes such as cell proliferation, apoptosis, glucose metabolism, transcription and cell migration. It has three isoforms (Akt1, 2, and 3) that have distinct and sometimes contrasting functions in different cancers. However, till date, most of the inhibitors are directed against Akt kinase generally which would not serve the purpose due to the lack of isoform selectivity and off-target toxicity. Therefore, the present study is an elementary step towards the demarcation of the natural inhibitors available from food sources and dietary supplements using in silico methods.

Objective: To demarcate the natural agents and general Akt kinase inhibitors into Akt Isoform-specific Inhibitors.

Method: The protein sequence alignment was achieved using PRALINE program. The modeling of Akt3 protein and its evaluation was performed by ModWeb Server and PROCHECK program respectively. The docking was performed by using Schrödinger Glide software.

Results: The protein sequence alignment has shown both the conserved as well as the non-conserved region of Akt isoforms. The structure of Akt3 was successfully modeled and evaluated. The molecular docking of natural agents and general Akt inhibitors has segregated them into Akt isoform-specific inhibitors based on the derived Glide Score (GScore).

Conclusion: Isoform-specific inhibition of Akt would have huge clinical significance and research should be commenced in preclinical and clinical settings.

Keywords:

Akt Isoforms, Natural Agents, Homology Modeling, Ramachandran plot, Docking, Schrödinger Glide

Affiliation:

Cancer Biology Laboratory and DBT-AIST International for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam 781 039, Cancer Biology Laboratory and DBT-AIST International for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam 781 039, Cancer Biology Laboratory and DBT-AIST International for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam 781 039, Cancer Biology Laboratory and DBT-AIST International for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam 781 039, Cancer Biology Laboratory and DBT-AIST International for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology, Guwahati, Assam 781 039



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