Ligand binding to anti-cancer target CD44 investigated by molecular simulations

• Published in: Journal of molecular modeling 2016-07, Vol.22 (7), p.165-165, Article 165
• Main Authors: Nguyen, Tin Trung, Tran, Duy Phuoc, Pham Dinh Quoc Huy, Hoang, Zung, Carloni, Paolo, Van Pham, Phuc, Nguyen, Chuong, Li, Mai Suan
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Binding Sites; Binding, Competitive - drug effects; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Humans; Hyaluronan Receptors - antagonists & inhibitors; Hyaluronan Receptors - chemistry; Hyaluronan Receptors - metabolism; Hyaluronic Acid - chemistry; Hyaluronic Acid - metabolism; Hydrogen Bonding; Ligands; Molecular Dynamics Simulation; Molecular Medicine; Molecular Structure; Original Paper; Protein Binding - drug effects; Protein Domains; Theoretical and Computational Chemistry; Thermodynamics
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-016-3029-6

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.