Computational Study and Design of Novel Chemotherapeutic Agents against Hepatocellular Carcinoma

Hepatocellular carcinoma is the fourth most common cause of cancer related fatality globally and has constituted a serious health care burden owing to dearth of effective systemic chemotherapeutic agents against this disease. In this study, a set of bioactive compounds with proven anticancer activities against HepG۲ cell lines were subjected to theoretical investigations via the use of QSAR modelling, molecular docking simulation, ADMET and drug-likeness evaluation. The validated QSAR model (R۲ = ۰.۹۴, R۲Adj = ۰.۹۳, Q۲LOO = ۰.۹۱, R۲Pred = ۰.۸۱) revealed the predominant influence of ZMIC۲ descriptor on the chemotherapeutic properties of the compounds. Optimization of the anticancer property of the most active compound (template) through its structural modification guided by ZMIC۲ descriptor in the model led to the design of more potent analogues; G-۱, G-۲, and G-۳ with predicted IC۵۰ value of ۹.۷۷ µM, ۲.۴۵ µM, and ۵.۵۰ µM, respectively. Molecular docking investigation of the designed ligands against the active sites of Aurora B kinase, the protein target found to be strongly involved in hepatocarcinogenesis, reveals that G-۱, G-۲, and G-۳ bind with ΔG value of -۸.۰ kcal/mol, -۷.۸ kcal/mol, and -۷.۷ kcal/mol, respectively. These values are higher and better compared to -۷.۵ kcal/mol recorded for the template molecule. Also, insilico drug-likeness and ADMET assessment of the novel ligands revealed that they possess good oral bioavailability, excellent pharmacokinetic and toxicity profiles. However, further invivo and invitro studies are required on the designed drug candidates to validate these claims.

کلیدواژه ها:

Hepatocellular Carcinoma ، HepG۲ ، ADMET ، Insilico ، QSAR