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Issue 14, 2019, Issue in Progress
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Fragment-centric topographic mapping method guides the understanding of ABCG2-inhibitor interactions

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Abstract

Understanding protein–ligand interactions 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 address this constraint, 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 pose 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 the structure of apo. Classical molecular simulation and accelerated molecular simulation are used to verify the accuracy of inhibitor screening and binding pose selection. Our study not only has gained insight for the development of novel specific ABCG2 inhibitors, but also has provided a general strategy in describing protein–ligand interactions.

Graphical abstract: Fragment-centric topographic mapping method guides the understanding of ABCG2-inhibitor interactions

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Publication details

The article was received on 28 Nov 2018, accepted on 01 Mar 2019 and first published on 08 Mar 2019


Article type: Paper
DOI: 10.1039/C8RA09789E
RSC Adv., 2019,9, 7757-7766
  • Open access: Creative Commons BY-NC license
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    Fragment-centric topographic mapping method guides the understanding of ABCG2-inhibitor interactions

    Y. Wu, X. Gao, X. Chen, S. Zhang, W. Wang, X. Sheng and D. Chen, RSC Adv., 2019, 9, 7757
    DOI: 10.1039/C8RA09789E

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