Comprehensive pharmacokinetic profiling and molecular docking analysis of natural bioactive compounds targeting oncogenic biomarkers in breast cancer.

in Scientific reports by Basim Othman, Saba Beigh, Mohammad A Albanghali, Abdulmajeed A A Sindi, Mohammed A Shanawaz, Mohamed Awad Elkarim Mohamed Ibahim, Dina Marghani, Yasser Kofiah, Navid Iqbal, Hina Rashid

TLDR

  • Scientists studied four natural compounds to see if they could help fight breast cancer. Berberine and Ellagic Acid showed promise due to their good pharmacokinetics and robust interactions with key proteins.
  • The findings suggest that these compounds could be useful additions to current breast cancer treatments, and future research should focus on understanding how they work and how they can be used to help patients.

Abstract

Breast cancer is one of the leading causes of death in women worldwide, highlighting the crucial need for novel and effective treatments. In this study, we look at the ability of four natural compounds i.e. Berberine, Curcumin, Withaferin A, and Ellagic Acid to target important breast cancer biomarkers such as B-cell lymphoma 2 (BCL-2), programmed death-ligand 1 (PDL-1), cyclin-dependent kinase 4/6 (CDK4/6) and fibroblast growth factor receptor (FGFR). These indicators have important roles in tumor development, survival, immune response, and cell cycle control, making them potential targets for future cancer treatments. Our study employs a variety of techniques, including pharmacokinetic profiling (ADME), molecular docking, and molecular dynamics simulations, to determine how successful these drugs could be in therapy. The pharmacokinetic investigation found that Berberine and Ellagic Acid stand out due to their high absorption and solubility, implying that they could be suitable for clinical application. When we ran docking simulations, we discovered substantial connections between these chemicals and the target proteins. Additionally, Berberine has a binding affinity of - 9.3 kcal/mol for BCL-2, indicating that it can impair the protein's cancer cell-protective activities. Ellagic Acid, on the other hand, has an even higher binding affinity for PDL-1 of - 9.8 kcal/mol, showing that it may be able to increase immune responses against tumors. Molecular dynamics simulations over 100 ns demonstrated the stability of these protein-ligand complexes. Interestingly, Ellagic Acid was found to be more structurally stable than Berberine throughout these simulations. We found consistent interactions between the chemicals and key residues in the target proteins. For example, Ellagic Acid (CID: 5281855) established persistent linkages with LYS43, ASP163, and VAL27, whereas Berberine (CID: 2353) interacted with VAL27, ALA41, and LEU152 throughout the simulation. In conclusion, the combination of good pharmacokinetics, robust interactions with cancer biomarkers, and stable complexes makes Berberine and Ellagic Acid interesting candidates for further investigation as natural inhibitors in breast cancer treatment. These findings establish the framework for future research into novel and inventive techniques to effectively combating breast cancer.

Overview

  • The study investigated the ability of four natural compounds to target important breast cancer biomarkers, aiming to identify novel and effective treatments.
  • The compounds, Berberine, Curcumin, Withaferin A, and Ellagic Acid, were evaluated using pharmacokinetic profiling, molecular docking, and molecular dynamics simulations.
  • The primary objective was to determine the potential of these compounds as inhibitors in breast cancer treatment, leveraging their ability to disrupt key protein-protein interactions.

Comparative Analysis & Findings

  • Berberine and Ellagic Acid demonstrated high absorption and solubility, making them suitable for clinical application.
  • Molecular docking simulations revealed significant interactions between the compounds and target proteins, with Berberine showing a binding affinity of -9.3 kcal/mol for BCL-2 and Ellagic Acid displaying a binding affinity of -9.8 kcal/mol for PDL-1.
  • Molecular dynamics simulations demonstrated the stability of the protein-ligand complexes, with Ellagic Acid exhibiting greater structural stability than Berberine.

Implications and Future Directions

  • The findings suggest that Berberine and Ellagic Acid are interesting candidates for further investigation as natural inhibitors in breast cancer treatment, given their favorable pharmacokinetics and robust interactions with cancer biomarkers.
  • Future research could focus on developing novel and inventive techniques to effectively combat breast cancer, such as combining these compounds with other therapeutic agents or exploring their potential in combination with immunotherapy.
  • It would be valuable to conduct further studies to elucidate the mechanisms underlying the interactions between these compounds and breast cancer biomarkers, as well as to assess their efficacy in preclinical models and eventually in clinical trials.
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