Theoretical Investigation and Design of Novel Anti-proliferative Agents against Hepatocellular Carcinoma from Benzimidazole-Chalcone derivatives

Hepatocellular carcinoma is recognized as a major cause of cancer-related deaths worldwide and has been a healthcare burden globally. In the search for novel chemotherapeutic agents for treating this disease, a set of benzimidazole-chalcone derivatives with proven inhibitory activities against HepG2 cancer cell line were subjected to QSAR modeling. Structural optimization of the most active derivatives guided by the dominant descriptors in the validated model (R2 = 0.93, R2Adj = 0.92, Q2LOO = 0.91, R2Pred = 0.81) led to the design of more potent analogs; H-1, H-2, and H-3, with predicted IC50 values of 26.07µM, 43.38µM, and 178.69 µM, respectively. Molecular docking simulations of these novel ligands against the active sites of epidermal growth factor receptor (EGFR) protein target recorded binding energy values of -8.4, -8.9, and -8.1 for H-1, H-2, and H-3, respectively. These values are better compared to -7.6 kcal/mol recorded for Doxorubicin, a standard drug for managing liver cancer used herein for quality assurance. Also, ADMET evaluation of the designed drug candidates reveals that they possess excellent pharmacokinetic and toxicity profiles. It is envisaged that the wealth of information obtainable from this work could help to discover and develop novel chemotherapeutic agents for treating systemic and early-stage hepatocellular carcinoma.