title: Ligand binding to anti-cancer target CD44 investigated by molecular simulations.
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.
authors.affiliation: Institute for Computational Sciences and Technology, SBI building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.
authors.forename: Tin Trung
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: University of Technology, Vietnam National University-Ho Chi Minh City, 268 Ly Thuong Kiet Street, District 10, Ho Chi Minh City, Vietnam.
authors.forename: Duy Phuoc
authors.initials: DP
authors.lastname: Tran
authors.affiliation: Institute for Computational Sciences and Technology, SBI building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam.|Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668, Warsaw, Poland.
authors.lastname: Pham Dinh Quoc Huy
authors.affiliation: Center for Molecular and NanoArchitecture (MANAR), Vietnam National University-Ho Chi Minh City, Quarter 6, Linh Trung Ward, Thu Duc District, Ho Chi Minh City, Vietnam.
authors.forename: Zung
authors.initials: Z
authors.lastname: Hoang
authors.affiliation: Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Juelich, Juelich, Germany. p.carloni@fz-juelich.de.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.affiliation: Stem Cell Research and Application Laboratory, University of Science, Vietnam National University, Ho Chi Minh City, Vietnam. pvphuc@hcmus.edu.vn.
authors.forename: Phuc
authors.initials: P
authors.lastname: Van Pham
authors.affiliation: Theoretical Physics Research Group, Ton Duc Thang University, Ho Chi Minh City, Vietnam. nguyenhahungchuong@tdt.edu.vn.|Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam. nguyenhahungchuong@tdt.edu.vn.
authors.forename: Chuong
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668, Warsaw, Poland. masli@ifpan.edu.pl.
authors.forename: Mai Suan
authors.initials: MS
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D008024:Ligands; D006820:Hyaluronic Acid
keywords: Breast cancer; CD44; F-19848A; Hyaluronan; Steered molecular dynamics; Traditional Chinese medicine