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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 type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): September 03, 2018
Effective date (End): January 06, 2019
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Antonia Tavares Do Amaral
Grantee:Lucas Gasparello Viviani
Supervisor abroad: Rebecca Claire Wade
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : 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.