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 Studios client version 184.108.40.206.16347 and the pharmacokinetic predictions have been made through ADMET SAR. The responsiveness towards 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.
Result: 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 shows that Kaempferol has favorable drug likeliness properties and bind 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 was having 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 an mTORC1 inhibitor against Hepatocellular carcinoma.
P. Siniprasad, Bhagyalakshmi Nair, Balasubramaniam, V., Sadanandan, P., Namboori, P. Krishnan K., and Lekshmi R Nath, “Evaluation of Kaempferol as AKT Dependent mTOR Regulator via Targeting FKBP-12 in Hepatocellular Carcinoma: an In silico Approach”, Letters in Drug Design & Discovery, 2020.