A network pharmacological approach to reveal the multidrug resistance reversal and associated mechanisms of acetogenins against colorectal cancer.

Multidrug Resistance (MDR) in tumors is caused by the over-expression of ATP Binding Cassette transporter proteins such as Multidrug Resistance Protein 1 and Breast Cancer Resistance Protein 1. This study focuses on identifying a MDR inhibitor among acetogenins (AGEs) of and also aims at predicting colorectal cancer (CRC) core targets of AGEs through a network pharmacological approach. Twenty-four AGEs were initially screened for their ADME properties. Molecular interaction studies were performed with the two proteins MRP1 and BCRP1. As the structure of MRP1 was not available, an inward-facing conformation of MRP1 was modeled. A Protein-protein interaction network was constructed for the correlating targets of CRC. KEGG pathway and Gene Ontology analysis were performed for the predicted CRC targets. We identified four lead AGEs: Muricatocin B, Annonacinone, Annonacin A and Annomuricin E having a higher binding affinity towards MDR proteins. MD simulation studies performed with the three lead AGEs and the MDR proteins showed that MRP1(DBD): Annomuricin E complex was stable throughout the simulation. Our analysis revealed ABCG2, ERBB2, STAT3, AR, SRC and ABCC1 as CRC targets of the lead molecules. The top 10 signaling pathways and functions of correlative CRC targets were also predicted. We conclude that the identified lead molecules might act as competitive inhibitors for reversing MDR in CRC. Additionally, network pharmacological studies established the correlative CRC targets and their mechanisms of action. Further experimental studies are needed to validate our findings. Communicated by Ramaswamy H. Sarma.