Resistance Protein ABCG2 And Its Inhibition Theoretical Study Of The Interaction Agent

Multidrug resistance(MDR)is a major cause of failure in cancer chemotherapy.ABCG2,a promiscuous drug efflux pump,has been extensively studied for its association with MDR due to overexpression in cancer cells.One way to overcome MDR is to apply potent inhibitors of ABC transporters to restore the sensitivity of the cells toward cytotoxic agents.However,the development of novel inhibitors has been confined due to the deficient knowledge of the interaction mechanism between inhibitors and ABCG2.Therefore,understanding protein-ligand interaction is crucial to drug discovery and design.However,it would be extremely difficult for the proteins which only have one available apo structure but multiple binding sites.To solve this problem,we carried out the following two tasks.The main contents are listed as follow:(1)Fragment-centric topographic mapping method guides the understanding of ABCG2-inhibitor interactionsHerein,a fragment-centric topographic mapping method(AlphaSpace software),was employed to map out concave interaction pockets at the assigned protein region.These pockets are used as complementary spaces to screen the known inhibitors for this specific binding site and to guide the molecular docking poses selection as well as protein-ligand interaction analysis.By mapping the shape of central cavity surface,we have tested the strategy against a multi-drug resistant transmembrane protein-ABCG2 to assist in generating a pharmacophore model for its inhibitors that is based on apo structure.Classical molecular simulation and accelerated molecular simulation were used to verify the accuracy of inhibitors screening and binding poses selection.Our study not only has gained gains insight for the development of novel specific ABCG2 inhibitors,but also has provides a general strategy in describing protein-ligand interactions.(2)Theoretical Insight into the Multiple Interactions of Quinazoline Inhibitors with ABCG2Herein,by employing chemical informatics,molecular dynamics simulations as well as binding interface analysis,we have modeled three typical classes of binding modes for quinazoline deviates depending on the substituents at position 2,4 and 6.In all classes,inhibitors can bind tightly to ABCG2 transporter and lock the global structure in an inward-facing conformation.This multiple interaction mechanism highlights the structural diversity of inhibitors targeting the center cavity,explains the importance of simultaneously binding to the top two pockets,and has significant implications for the rational design of novel high-potency ABCG2 inhibitors and the structural modification of existing inhibitors.In addition,lipophilicity and planarity of a molecule are also presupposed to be vital for a potent inhibitor.The present study has developed a comprehensive computational strategy to understand the protein–ligand interaction with the help of MD simulations.We expect that our current studies can provide theoretical aids for designs of high effective drugs targeting ABCG2 to cure diseases such as cancer resistant.