Physicochemical characterization of paclitaxel prodrugs with cytochrome 3A4 to correlate solubility and bioavailability implementing molecular docking and simulation studies

Abstract

Prodrugs are biologically inactive drug molecules that may be developed through rational drug design with an objective to improve a drug’s pharmaceutical and pharmacokinetic properties. Paclitaxel, a highly potent anticancer drug, is directed against many cancers like breast cancer, ovarian cancer, lung cancer, head and neck tumors, non-small cell lung cancer, and Kaposi’s sarcoma, etc. Along with its excellent antitumor activity the drug had a major limitation of low water solubility. To overcome this limitation of this nanomolar active drug many prodrugs were formed in the past. Though increase in the solubility of the drug was obtained but that may or may not account for its increase in bioavailability. CYP3A4 liver enzymes are responsible for the metabolism of fifty percent of the drugs and are major metabolizing enzyme for paclitaxel. Phosphate prodrugs are well known to account the insolubility of many drugs and thus increasing their bioavailability also. In this study, we calculated the ADMET properties of a dataset of twenty phosphate prodrugs of paclitaxel. On the basis of reflection of three favourable properties, ten prodrugs were chosen for further docking studies against CYP3A4. Finally, three prodrugs showing unfavourable binding affinities were selected for Molecular Dynamics Simulations and from this in-silico study we identified that all the three selected prodrugs were unstable as compared to the paclitaxel. The instability of these prodrugs showed their lesser interaction with the CYP3A4 and hence contributing more towards its bioavailability. Thus the three suggested prodrugs those were studied in-silico for oral bioavailability can be further validated for gastrointestinal cancer. Communicated by Ramaswamy H. Sarma