Use of molecular dynamics (MD) simulations to study human ecto-5'-nucleotidase (ecto-5'NT, CD73) flexibility and TRAPP (Transient Pockets in Proteins) for protein binding site dynamics analyses

• Grant number: 18/06381-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: September 03, 2018
• End date: January 06, 2019
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Organic Chemistry
• Principal Investigator: Antonia Tavares Do Amaral
• Grantee: Lucas Gasparello Viviani
• Supervisor: Rebecca Claire Wade
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Heidelberg Institute for Theoretical Studies (HITS), Germany
• Associated to the scholarship: 14/07248-0 - Virtual screening search for inhibitors of human ecto-5'-nucleotidase and of Mycobacterium tuberculosis thiorredoxin reductase: models generation and experimental validation, BP.DD

Abstract

Ecto-5'-nucleotidase (ecto-5'NT, CD73) is a Zn2+-binding glycosylphosphatidylinositol (GPI)-anchored homodimeric enzyme, which hydrolyses AMP to adenosine, acting as a major control point for the extracellular provision of this signalling molecule. Human ecto-5'NT has been found to be expressed by several types of tumour cells, triggering immunosuppressive pathways in the tumour microenvironment. Accordingly, ecto-5'NT has been shown to promote tumour growth and metastasis in vivo, emerging as a promising drug target for cancer. Human ecto-5'NT 3D structure was elucidated by X-ray crystallography in 2012, providing insights to structure-based design of inhibitors for this target enzyme. However, there are only few ecto-5'-NT inhibitors described in the literature so far. Recently, in our group, virtual screening (VS) models to search for novel human ecto-5'NT inhibitors have been generated and applied to the ZINC database (~23x106 compounds). Among the selected and tested compounds, 7 showed IC50 values in the micromolar range. To date, the generated VS models were obtained using static 3D crystal structures of ecto-5'NT as starting points. It is known, however, that this often a limited representation for ligand-protein recognition modelling, since structural flexibility plays a relevant role in the binding process. Here, to contribute for further VS campaigns, we aim to study human ecto-5'NT structure flexibility, using molecular dynamics (MD) simulations. Additionally, to account for ecto-5'NT binding site dynamics, we intend to use TRAPP (Transient Pocket in Proteins), a software platform developed by Kokh et al. for tracking, analysis and visualization of binding pocket variations along a protein motion trajectory. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

VIVIANI, LUCAS G.; PICCIRILLO, ERIKA; ULRICH, HENNING; AMARAL, ANTONIA T-DO. Virtual Screening Approach for the Identification of Hydroxamic Acids as Novel Human Ecto-5 `-Nucleotidase Inhibitors. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 2, p. 621-630, FEB 2020. (14/07248-0, 12/50880-4, 18/24678-0, 12/06633-2, 18/07366-4, 13/07937-8, 18/06381-0)

VIVIANI, LUCAS G. G.; KOKH, DARIA B. B.; WADE, REBECCA C. C.; DO AMARAL, ANTONIA T.. Molecular Dynamics Simulations of the Human Ecto-5′-Nucleotidase (h-ecto-5′-NT, CD73): Insights into Protein Flexibility and Binding Site Dynamics. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 63, n. 15, p. 17-pg., 2023-08-02. (14/07248-0, 21/10514-8, 13/07937-8, 18/06381-0)

VIVIANI, LUCAS G.; PICCIRILLO, ERIKA; ULRICH, HENNING; AMARAL, ANTONIA T-DO. Virtual Screening Approach for the Identification of Hydroxamic Acids as Novel Human Ecto-5 '-Nucleotidase Inhibitors. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 2, p. 10-pg., 2020-02-01. (13/07937-8, 12/50880-4, 18/06381-0, 18/24678-0, 12/06633-2, 18/07366-4, 14/07248-0)