Article ; Online: Homology Modeling and Molecular Dynamics Simulations of Trypanosoma cruzi Phosphodiesterase b1.
2021 Volume 19, Issue 1, Page(s) e202100712
Abstract: Cyclic nucleotide phosphodiesterases have been implicated in the proliferation, differentiation and osmotic regulation of trypanosomatids; in some trypanosomatid species, they have been validated as molecular targets for the development of new ... ...
| Abstract | Cyclic nucleotide phosphodiesterases have been implicated in the proliferation, differentiation and osmotic regulation of trypanosomatids; in some trypanosomatid species, they have been validated as molecular targets for the development of new therapeutic agents. Because the experimental structure of Trypanosoma cruzi PDEb1 (TcrPDEb1) has not been solved so far, an homology model of the target was created using the structure of Trypanosoma brucei PDEb1 (TbrPDEb1) as a template. The model was refined by extensive enhanced sampling molecular dynamics simulations, and representative snapshots were extracted from the trajectory by combined clustering analysis. This structural ensemble was used to develop a structure-based docking model of the target. The docking accuracy of the model was validated by redocking and cross-docking experiments using all available crystal structures of TbrPDEb1, whereas the scoring accuracy was validated through a retrospective screen, using a carefully curated dataset of compounds assayed against TbrPDEb1 and/or TcrPDEb1. Considering the results from in silico validations, the model may be applied in prospective virtual screening campaigns to identify novel hits, as well as to guide the rational design of potent and selective inhibitors targeting this enzyme. |
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| MeSH term(s) | 3',5'-Cyclic-AMP Phosphodiesterases/chemistry ; 3',5'-Cyclic-AMP Phosphodiesterases/metabolism ; Amino Acid Sequence ; Area Under Curve ; Binding Sites ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Structure, Tertiary ; Protozoan Proteins/chemistry ; Protozoan Proteins/metabolism ; ROC Curve ; Sequence Alignment ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/metabolism ; Trypanosoma brucei brucei/enzymology ; Trypanosoma cruzi/enzymology |
| Chemical Substances | Protozoan Proteins ; Small Molecule Libraries ; 3',5'-Cyclic-AMP Phosphodiesterases (EC 3.1.4.17) ; PDEB1 protein, Trypanosoma brucei (EC 3.1.4.17) |
| Language | English |
| Publishing date | 2021-12-16 |
| Publishing country | Switzerland |
| Document type | Journal Article |
| ZDB-ID | 2139001-0 |
| ISSN | 1612-1880 ; 1612-1872 |
| ISSN (online) | 1612-1880 |
| ISSN | 1612-1872 |
| DOI | 10.1002/cbdv.202100712 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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