Pharmacokinetic predictions of ROS-mediated targets and genotoxin combinations via multiple ligand simultaneous docking and ROS evaluation in vitro using HepG2 cell lines

Although combination therapy is known for its high efficacy, reduced side effects and drug resistance, toxicity remains a major drawback. Some of the genes are likely to induce hepatotoxicity through ROS-mediated mechanisms when a drug is metabolized alone or in combination in the liver. To address this, we have developed a scientific approach to predict the toxicity of different genotoxin combinations and validate their interactions with various targets. The current study is an extensive study of our previous set of in vivo rat liver microarray data processed using R studio for their functional analysis. About five combinations of genotoxins such as CPT/ETP, CPT/CPL, ETP/CPL, CP/CPT and EES/CP along with their differential gene expression targeting Chemical carcinogenesis—ROS are chosen for this study. We aim to examine the binding affinity of different genotoxin combinations using in silico multiple ligand simultaneous docking (MLSD) and are then bio-evaluated for cytotoxicity in vitro using human hepatocellular carcinoma cell lines (HepG2) with the MTT assay. As a result, dose–response cytotoxicity with its strength of interactions and a significant variance in ROS levels in the treated cells is observed compared to their IC 50 values. Out of 5 combinations such as CPT/CPL, ETP/CPL and EES/CP are found not only to be significantly cytotoxic but also induce oxidative stress specifically above their IC 50 values with good and moderate binding interactions ensuring their toxicity. On the contrary, the safe combinations are found to be CTP/ETP and CP/CPT possibly with no and tolerable adverse effects standing as preliminary information for researchers in drug design and development.