uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Assaying phenothiazine derivatives as trypanothione reductase and glutathione reductase inhibitors by theoretical docking and Molecular Dynamics studies
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Physical Chemistry.
2009 (English)In: Journal of Molecular Graphics and Modelling, ISSN 1093-3263, E-ISSN 1873-4243, Vol. 28, no 4, 371-381 p.Article in journal (Refereed) Published
Abstract [en]

A theoretical docking study, conducted on a sample of previously reported phenothiazine derivatives, at the binding sites of Trypanosoma cruzi trypanothione reductase (TR) and human erythrocyte glutathione reductase (GR), examines interaction energies (affinities) towards the parasite enzyme to check for selectivity with respect to the human counterpart. Phenothiazine compounds were previously shown to be TR inhibitors. The analysis of data collected from the docking procedure was undertaken both from the numeric and graphical standpoints, including the comparison of force field, energies, molecular contacts and spatial location of the different orientations that ligands acquired at the binding sites. Molecular Dynamics simulations were also carried out for derivatives with known quantitative inhibition kinetics (Ki). The results indicate that (positively) charged phenothiazines attain larger interaction energies at TR active site, in line with previous experimental information. Suitable molecular size and shape is also needed to complement the electrostatic effect, as clearly evidenced by graphical analysis of output docked conformations. Docking energies values are reasonably well correlated with those obtained by Molecular Dynamics as well as with the experimental Ki values, confirming once again the validity of this type of scoring methods to rapidly assess ligand–receptor affinities. Alongside newly discovered classes of TR inhibitors, the promazine (N-alkylaminopropylphenothiazine) nucleus should still be considered when good candidates are sought as leaders for selective TR inhibition.

Place, publisher, year, edition, pages
2009. Vol. 28, no 4, 371-381 p.
Keyword [en]
Chagas' disease, Phenothiazines, Trypanothione reductase, Binding affinity, Theoretical docking, Molecular Dynamics
National Category
Chemical Sciences
Research subject
Physical Chemistry
URN: urn:nbn:se:uu:diva-110898DOI: 10.1016/j.jmgm.2009.09.003ISI: 000272133500008OAI: oai:DiVA.org:uu-110898DiVA: diva2:278880
Available from: 2009-11-30 Created: 2009-11-30 Last updated: 2010-06-23Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text
By organisation
Physical Chemistry
In the same journal
Journal of Molecular Graphics and Modelling
Chemical Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 406 hits
ReferencesLink to record
Permanent link

Direct link