Molecular Docking and Pharmacokinetic Profiling of Nab-paclitaxel as Advanced Chemotherapeutic Agent Against HER-2 Positive Breast Cancer Patients

Abstract

Objective: The main objective of the study is to explore the potential molecular benefits of Nab-paclitaxel as an effective advanced chemotherapeutic agent for HER2-positive breast cancer patients. Specifically, the study aims to assess Nab-paclitaxel as a potential drug candidate for breast cancer treatment.

Methods: This study used bioinformatics and cheminformatics to analyze the HER2 signaling pathway and its possible interactions with Nab-Paclitaxel. This involves using pharmacokinetic profiling software to evaluate its physicochemical properties, analyzing its potential impact on gene expression modulation, and assessing its binding affinity to the HER2 receptor through molecular docking.

Result: The results indicate that the most favorable docking pose occurs between chain B of the HER-2 receptor and Paclitaxel, with a binding energy of -9.4 kcal/mol. Notably, a hydrogen bond is observed in ARG849, with 3.0 Angstrom (Å). Previous research highlights Paclitaxel's impact on breast cancer patients' genes, particularly the ABCB1 gene responsible for P-glycoprotein production, contributing to drug resistance in chemotherapy. Nab-paclitaxel exhibits potential ease of metabolism, as it minimally inhibits drug-metabolizing cytochrome P450 enzymes. Additionally, despite initial concerns related to drug-likeness parameters and molecular weight discrepancies, the pharmacokinetic profile of Nab-Paclitaxel suggests improvements in delivery facilitated by an albumin-supported nanoparticle delivery mechanism.

Conclusion: The binding energy confirms the secure docking of ligands to receptors, suggesting the stability of the interaction between them. Nevertheless, prolonged administration of Paclitaxel poses the risk of inducing drug resistance, a significant factor contributing to treatment failure. This emphasizes the need to explore new candidate drug combinations or identify alternative drug-binding interaction sites. Such endeavors hold the potential to enhance the effectiveness of drug treatments and address challenges associated with prolonged Paclitaxel use.

Keywords: ABCB1; ARG849; Cytochrome P450; HER2; nab-paclitaxel.

Figure 1

Two-Dimensional Illustration of the Amino Acid Residues Involved in Binding between the Paclitaxel and Active Site of HER-2. 1a shows the conventional and Pi-donor H-bonds of Paclitaxel with Chain A of HER-2, and 2b depicts the hydrophobic interactions between Chain B of HER-2 and Paclitaxel.

Figure 2

Three-Dimensional Depiction of Molecular Interaction of Paclitaxel to HER-2 Active Site. 2a indicates the position of Paclitaxel on Chain 1 and 2b shows Paclitaxel interaction on Chain 2 in the HER-2 active site pocket.

Figure 3

Predicted Classes of Proteins that Interact with Paclitaxel as Determined by Swiss Target