Acridines are known deoxyribonucleic acid (DNA) intercalators. Accordingly, the interaction of the present acridine derivatives within the DNA double helix was extensively investigated via a sophisticated ensemble of molecular simulation techniques. The results showed that an intricate balance of molecular features contributed to the thermodynamic/kinetics aspects of acridines/DNA binding and, hence, to the ultimate STR for these series of HCV RdRp inhibitors. Among these factors, the length of the large side chain R was found to play a primary role in determining DNA binding strength and, hence, cellular toxicity.
