A Multi-Method Study Molecular Docking+Network Pharmacology+MD Simulation

Background

Breast cancer is a type of cancer that begins in the cells of the breast. It is one of the most common malignant tumors in women worldwide, and although it can occur in men, the incidence is much lower. Ascorbic acid is a commonly used drug for the treatment of breast cancer, but the exact molecular mechanisms underlying its effectiveness remain unclear. In view of this, on April 13, 2024, Prof. Anil Kumar Yadav's team published the results of their paper in Molecular Diversity.

In this study, the researchers used a combination of network pharmacology, molecular docking and molecular dynamics simulations in order to reveal the most potent phytochemicals in Ascophyllum officinale in order to delve into their interactions with target proteins in breast cancer therapy. The researchers identified 18 active compounds and 89 related targets, mainly associated with a variety of biological processes such as lipid metabolism, signaling pathways in diabetes, viral infections and cancer-related pathways. Molecular docking analysis revealed that the two most active compounds, formononetin and ascomycetin epoxide, exhibited strong binding to the target protein AKT1. Through molecular dynamics simulations, they found that the ascomycetin epoxide-AKT1 complex exhibited greater structural stability and lower interaction energies compared to the soy sterol-AKT1 complex. The results suggest that asiatica exerts its role in breast cancer therapy through a synergistic multi-component and multi-target approach. In addition, they suggest that the ascomycetes epoxidized alcohols targeting AKT-1 represent the most potent compounds, providing valuable insights into the molecular mechanisms underlying their role in breast cancer therapy.

Methods and Discussion

It is known that asiatica has anticancer activity against several targets in breast cancer, but the active components found in asiatica and the underlying molecular mechanisms of their action have not been systematically investigated. Figure 2 shows the route of action of intracellular enzymes in breast cancer.

Therefore, the aim of the reported work was to develop a network between phytochemicals and targets that would lead to the identification of active compounds present in Asclepias that could be used to inhibit carcinogenic agents using computerized methods. The researchers used GROMACS software for molecular dynamics simulations. The Particle Mesh Ewald (PME) method was used to calculate long-range electrostatic interactions during the simulations.

1. Targets identified for action in breast cancer

An initial search of 7684 targets from the GeneCards database and 237 targets from the OMIM database was performed. After eliminating duplicate entries, a total of 7525 relevant targets were retained. Through this analysis, the researchers identified 18 intersections between ascoma-related targets and breast cancer-related targets (Figure 3). Notably, all of these intersecting targets were associated with differentially expressed genes in the breast cancer dataset.

2. PPI network analysis

The PPI network of AKT-1 is shown in Figure 3a. The 18 expected targets were imported into STRING for PPI analysis. In this PPI network, there are 146 nodes connected by 3412 edges as shown in Figure 3b. Network centrality metrics, including degree centrality, BC and CC, were used to assess the network properties of individual compounds or the entire network and thus node importance.

3. Molecular dynamics simulation

Molecular dynamics simulations play an important role in scientific research, especially in understanding complex molecular and biochemical processes. By numerically solving Newton's equations of motion, MD provides insight into the behavior of molecular dynamics at the atomic level. It helps to predict molecular interactions, conformational changes and thermodynamic properties. Figure 4 shows the chemical structures of Formononetin and Ascorbyl epoxide alcohols, as well as the conformation of their respective complexes with AKT-1, and the residues involved in their interactions.

Research summary and future perspectives

Although there have been in vitro and in vivo animal studies, as well as a number of clinical cases exploring its potential in cancer therapy, there is still a lack of comprehensive studies using a computerized pharmacological approach combining docking and kinetic simulations to unravel the active ingredients, potential targets, and pharmacological mechanisms of ascomycetes in the treatment of breast cancer. Molecular dynamics simulations confirmed the superiority of asiatica epoxide alcohol and AKT-1 with low binding energy and structural stability. This study lays a theoretical foundation for the application of asiatica in breast cancer therapy and provides guidance for further experimental studies.

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