In silico approach to target PI3K/Akt/mTOR axis by selected Olea europaea phenols in PIK3CA mutant colorectal cancer

Abstract

Worldwide disease burden of colorectal cancer (CRC) increasing alarmingly, but a suitable therapeutic strategy is not available yet. Abnormal activation of the PI3K/Akt/mTOR signalling because of mutation in the PIK3CA gene is a driving force behind CRC development. Therefore, this study aimed to comprehensively characterise the potential of phenolic compounds from Olea europaea against the PI3K/Akt/mTOR axis by using in silico methodologies. Molecular docking was utilised to study key interactions between phenolic compounds of O. europaea and target proteins PI3K, Akt, mTOR with reference to known inhibitor of target. Drug likeness and ADME/T properties of selected phenols were explored by online tools. Dynamic properties and binding free energy of target-ligand interactions were studied by molecular dynamic simulation and MM-PBSA method respectively. Molecular docking revealed apigenin, luteolin, pinoresinol, oleuropein, and oleuropein aglycone as the top five phenolic compounds which showed comparable/better binding affinity than the known inhibitor of the respective target protein. Drug likeness and ADME/T properties were employed to select the top three phenols namely, apigenin, luteolin, and pinoresinol which shown to bind stably to the catalytic cleft of target proteins as confirmed by molecular dynamics simulations. Therefore, Apigenin, luteolin, and pinoresinol have the potential to be used as the non-toxic alternative to synthetic chemical inhibitors generally used in CRC treatment as they can target PI3K/Akt/mTOR axis. Particularly, pinoresinol showed great potential as dual PI3K/mTOR inhibitor. However, this study needs to be complemented with future in vitro and in vivo studies to provide an alternative way of CRC treatment.

Communicated by Ramaswamy H. Sarma

Keywords:

• Olive phenolic compounds
• apigenin
• pinoresinol
• molecular docking
• molecular dynamics simulation

Disclosure statement

Authors declares no competing interest.

Authors’ contributions

A.S. conceived and planned the manuscript with D.N.; A.S. performed the literature review. A.S. and T.K. performed experiments. T.K. analysed the molecular docking and molecular dynamic simulations results. A.S. analysed drug likeness and ADME/T results. A.S. and T.K. prepared the figures and tables. A.S., D.N. and T.K. wrote manuscript. D.N. critically edited manuscript. All authors read and approved the final manuscript.

Additional information

Funding

This work was supported by Department of Science and Technology, Govt. of India (DST)- Inspire faculty research grant (DST/INSPIRE/04/2017/000675) and Maulana Abul Kalam Azad University of Technology, West Bengal (MAKAUT, WB) research seed grant to D.N. A.S was supported by fellowship from Council of Scientific and Industrial Research (CSIR), Govt. of India.