Evaluation of Kaempferol as AKT Dependent mTOR Regulator via Targeting FKBP-12 in Hepatocellular Carcinoma: An In silico Approach
Authors: Siniprasad Pooja , Nair Bhagyalakshmi , Balasubramaniam Vaisali , Sadanandan Prashanth , Namboori Puliyapally Krishnan , Nath Lekshmi Reghu 
Published: June 2020

Background:
Hepatocellular carcinomas (HCCs) are inherently chemotherapy-resistant
tumors with about 30-50% activation of PI3K/Akt/mTOR pathway, and this pathway is not aberrant
in normal cells. Therefore, targeting the PI3K/Akt/mTOR pathway has become a promising strategy
in drug designing to combat liver cancer. Recently, many studies with phytochemicals suggest few classes
of compounds, especially flavonoids, to be useful in down-regulating the PI3K/Akt/mTOR pathway corresponding
to HCC. In the present study, an attempt is made to explore flavonoids, from which the best
mTORC1 inhibitor against hepatocellular carcinoma is selected using computational molecular modeling.

Methods:
In the present study, we performed a virtual screening method with phytochemicals of
flavonoid category. To ensure proper bioavailability and druggability, pharmacokinetic and interaction
parameters have been used to screen the molecules. The target protein molecules have been selected
from the RCSB. The interaction studies have been conducted using Biovia Discovery Studio
client version 17.2.0.1.16347 and the pharmacokinetic predictions have been made through ADMET
SAR. The responsiveness towards the regulation of the mTOR pathway varies from person to person,
demanding a pharmacogenomic approach in the analysis. The genetic variants (Single Nucleotide
Variants-SNVs) corresponding to the mutations have been identified.

Results and Discussion:
The study identified phytoconstituents with better interaction with receptor
FKBP12, a Rapamycin binding domain which is the target of Rapamycin and its analogues for
mTORC1 inhibition in HCC. Another protein, ‘AKT serine/threonine-protein kinase’ has been identified,
which is associated with activation of mTORC1. The molecular interaction studies (docking
studies) and ADMET (absorption, distribution, metabolism, excretion and toxicity) analysis were
used to identify the affinity between selected phytoconstituents as mTORC1 inhibitor against Hepatocellular
carcinoma. The docking studies support Kaempferol to be a potential ligand with docking
score values of 33.4 (3CQU-3D structure of AKT1)] and 27.3 (2FAP-3D structure of FRB domain
of mTOR) respectively as compared to that of standard drug Everolimus with 24.4 (3CQU-3D structure
of AKT1) and 20.1 (2FAP-3D structure of FRB domain of mTOR) respectively. Docking studies
along with ADMET results show that Kaempferol has favorable drug likeliness properties and
binds to the same active site (site1) of the targeted proteins (3CQU-3D structure of AKT1) and
(2FAP-3D structure of FRB domain of mTOR) where the standard drug Everolimus is known to
bind.

Conclusion:
The study exhibited that Kaempferol had a better binding affinity towards the receptor
FKBP12, a Rapamycin Binding Domain and AKT serine/threonine-protein kinase resulting in its
better efficacy in the mTORC1 inhibition as when compared with standard drug Everolimus against
HCC. To the best of our knowledge, no studies have been reported on Kaempferol as mTORC1 inhibitor
against Hepatocellular carcinoma.