All submissions of the EM system will be redirected to Online Manuscript Submission System. Authors are requested to submit articles directly to Online Manuscript Submission System of respective journal.

Abstract

In silico and In vitro Perspective to Elucidate the Anticancer Effect of Natural Compound Hesperetin in Inhibiting Mammalian Target of Rapamycin Pathway

Author(s): S. S. Jaganathan, Gloria Jemmi Christobel Robinson, Abirami Padmanaban, Shila Samuel and V. Radhakrishnan*
Department of Biochemistry, VRR Institute of Biomedical Science (Affiliated to University of Madras), Chennai 600056, 1Department of Biochemistry, V.V. Vanniaperumal College for Women, Virudhunagar 626001, Tamil Nadu, India

Correspondence Address:
V. Radhakrishnan, Department of Biochemistry, V.V. Vanniaperumal College for Women, Virudhunagar 626001, Tamil Nadu, India, E-mail: [email protected]


In this study we intended to perform in silico and in vitro analysis of naturally derived flavonoid, hesperetin as a promising mammalian target of rapamycin inhibitor. This study features in silico screening of natural compound hesperetin against mammalian target of rapamycin FK506 binding proteins 12 domain by using Schrodinger glide based virtual screening and further molecular dynamics simulation was done to infer the stability of complex formation. Mammalian target of rapamycin co-crystallized with P2X (a known inhibitor of mTOR) (Protein Data Bank ID: 4JT5) was used for reference guided docking protocol. Then in vitro analysis applying hesperetin for cell viability followed by protein expressions in ovarian PA-1 and MCF-7 breast cancer cell lines were performed dose dependently. in silico molecular docking and dynamic studies with mammalian target of rapamycin protein revealed that hesperetin was found to be a potent compound that could inhibit the FK506 binding proteins 12 domain of mammalian target of rapamycin. The in vitro studies with hesperetin on PA-1 and MCF-7 breast cancer cell lines, found that hesperetin in a dose dependent manner significantly reduced the phosphorylation of mammalian target of rapamycin on Serine 2448 a marker for mammalian target of rapamycin complex 1 activity, as well as phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 and Ribosomal protein S6 kinase beta-1 which are downstream molecules of mammalian target of rapamycin was also significantly inhibited. To the best of our knowledge this is the first study that brings up the scientific evidence for the efficacy of hesperetin in inhibiting mammalian target of rapamycin with a similar docking score to the native ligand and also in a dose dependent manner in PA-1 human ovarian cancer cells and MCF-7 breast cancer cells, as an anticancer agent with further studies in near future.

Full-Text | PDF

 
 
Google scholar citation report
Citations : 53647

Indian Journal of Pharmaceutical Sciences received 53647 citations as per google scholar report