Ligand binding to anti-cancer target CD44 investigated by molecular simulations |
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Authors: | Tin Trung Nguyen Duy Phuoc Tran Pham Dinh Quoc Huy Zung Hoang Paolo Carloni Phuc Van Pham Chuong Nguyen Mai Suan Li |
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Affiliation: | 1.Institute for Computational Sciences and Technology,Ho Chi Minh City,Vietnam;2.University of Technology,Vietnam National University–Ho Chi Minh City,Ho Chi Minh City,Vietnam;3.Institute of Physics,Polish Academy of Sciences,Warsaw,Poland;4.Center for Molecular and NanoArchitecture (MANAR),Vietnam National University–Ho Chi Minh City,Ho Chi Minh City,Vietnam;5.Computational Biomedicine,Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Juelich,Juelich,Germany;6.Stem Cell Research and Application Laboratory,University of Science, Vietnam National University,Ho Chi Minh City,Vietnam;7.Theoretical Physics Research Group,Ton Duc Thang University,Ho Chi Minh City,Vietnam;8.Faculty of Applied Sciences,Ton Duc Thang University,Ho Chi Minh City,Vietnam |
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Abstract: | CD44 is a cell-surface glycoprotein and receptor for hyaluronan, one of the major components of the tumor extracellular matrix. There is evidence that the interaction between CD44 and hyaluronan promotes breast cancer metastasis. Recently, the molecule F-19848A was shown to inhibit hyaluronan binding to receptor CD44 in a cell-based assay. In this study, we investigated the mechanism and energetics of F-19848A binding to CD44 using molecular simulation. Using the molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) method, we obtained the binding free energy and inhibition constant of the complex. The van der Waals (vdW) interaction and the extended portion of F-19848A play key roles in the binding affinity. We screened natural products from a traditional Chinese medicine database to search for CD44 inhibitors. From combining pharmaceutical requirements with docking and molecular dynamics simulations, we found ten compounds that are potentially better or equal to the F-19848A ligand at binding to CD44 receptor. Therefore, we have identified new candidates of CD44 inhibitors, based on molecular simulation, which may be effective small molecules for the therapy of breast cancer. |
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