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Molecules 2016, 21(8), 1028; doi:10.3390/molecules21081028

Glutamine Synthetase Drugability beyond Its Active Site: Exploring Oligomerization Interfaces and Pockets

UCIBIO, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
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Academic Editors: James W. Gauld and Leif A. Eriksson
Received: 8 June 2016 / Revised: 1 August 2016 / Accepted: 4 August 2016 / Published: 8 August 2016
(This article belongs to the Special Issue Computational Design: A New Approach to Drug and Molecular Discovery)
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Abstract

Background: Glutamine synthetase (GS) is a crucial enzyme to the nitrogen cycle with great commercial and pharmaceutical value. Current inhibitors target the active site, affecting GS activity indiscriminately in all organisms. As the active site is located at the interface between two monomers, the protein-protein interface (PPI) of GSs gains a new role, by providing new targets for enzyme inhibition. Exploring GSs PPI could allow for the development of inhibitors selective for specific organisms. Here we map the PPI of three GSs—human (hsGS), maize (zmGS) and Mycobacterium tuberculosis (mtGS)—and unravel new drugable pockets. Methods: The PPI binding free energy coming from key residues on three GSs from different organisms were mapped by computational alanine scan mutagenesis, applying a multiple dielectric constant MM-PBSA methodology. The most relevant residues for binding are referred as hot-spots. Drugable pockets on GS were detected with the Fpocket software. Results and Conclusions: A total of 23, 19 and 30 hot-spots were identified on hsGS, zmGS and mtGS PPI. Even possessing differences in the hot-spots, hsGS and zmGS PPI are overall very similar. On the other hand, mtGS PPI differs greatly from hsGS and zmGS PPI. A novel drugable pocket was detected on the mtGS PPI. It seems particularly promising for the development of selective anti-tuberculosis drugs given its location on a PPI region that is highly populated with hot-spots and is completely different from the hsGS and zmGS PPIs. Drugs targeting this pockets should be inactive on eukaryotic GS II enzymes. View Full-Text
Keywords: protein-protein interactions; computational alanine scanning mutagenesis; drugable pockets; glutamine synthetase; Mycobacterium tuberculosis; human; maize; inhibition; drug discovery protein-protein interactions; computational alanine scanning mutagenesis; drugable pockets; glutamine synthetase; Mycobacterium tuberculosis; human; maize; inhibition; drug discovery
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Moreira, C.; Ramos, M.J.; Fernandes, P.A. Glutamine Synthetase Drugability beyond Its Active Site: Exploring Oligomerization Interfaces and Pockets. Molecules 2016, 21, 1028.

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