Potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches

Background & Hypothesis: The parasitic protozoa from the order Trypanosomatida relies exclusively on glycolysis for its survival in the mammalian hosts. As a corollary, the enzymes in this pathway have been recognised as chemotherapeutic targets. Phosphoglycerate mutase (iPGAM), which is the se...

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Main Authors:	Ahmad Fuad, Fazia Adyani, Walkinshaw, Malcolm D., Fothergill-Gilmore, Linda A., Houston, Dr.
Format:	Conference or Workshop Item
Language:	English
Published:	Academy of Medicine, Singapore 2015
Subjects:	Q Science (General)
Online Access:	http://irep.iium.edu.my/45423/ http://irep.iium.edu.my/45423/ http://irep.iium.edu.my/45423/1/45423.pdf

id	iium-45423
recordtype	eprints
spelling	iium-454232017-12-27T02:19:05Z http://irep.iium.edu.my/45423/ Potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches Ahmad Fuad, Fazia Adyani Walkinshaw, Malcolm D. Fothergill-Gilmore, Linda A. Houston, Dr. Q Science (General) Background & Hypothesis: The parasitic protozoa from the order Trypanosomatida relies exclusively on glycolysis for its survival in the mammalian hosts. As a corollary, the enzymes in this pathway have been recognised as chemotherapeutic targets. Phosphoglycerate mutase (iPGAM), which is the seventh enzyme in the pathway, is of particular interest because it possesses no structural and biochemical relationship with the corresponding enzyme in human. This enzyme has also been validated as an attractive therapeutic target for the treatment of trypanosomatid diseases. The aim of this work is to identify small molecules or compounds that could potentially be developed into potent inhibitors of trypanosomatid iPGAMs through in silico approaches. Methods: In the search for novel inhibitors, a ligand-based virtual screening programme, Ultra Fast Shape Recognition with Atom Types (UFSRAT), was utilised to screen for compounds resembling the substrate/product of iPGAM (3-phosphoglycerate/2phosphoglycerate), before a structure-based approach was applied using AutoDock Vina and COmbining Docking And Similarity Search (CODASS) programmes. The inhibitory effects of selected compounds were subsequently tested by monitoring the oxidation of nicotinamide adenine dinucleotide (NADH) through a continuous coupled assay system. Results: The results revealed that out of this collection of compounds, 7 compounds inhibited iPGAM's activity, with 1 compound from virtual screening analysis exhibited substantial inhibition (14% remaining activity). Discussion & Conclusion: Taken together, the findings from this study indicate that compounds which were discovered through in silico approaches have potentials to be developed as novel drugs that specifically target trypanosomatid iPGAMs. Academy of Medicine, Singapore 2015-10 Conference or Workshop Item PeerReviewed application/pdf en http://irep.iium.edu.my/45423/1/45423.pdf Ahmad Fuad, Fazia Adyani and Walkinshaw, Malcolm D. and Fothergill-Gilmore, Linda A. and Houston, Dr. (2015) Potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches. In: Singapore Health and Biomedical Congress 2015, 2-3 October 2015, Singapore. http://www.annals.edu.sg/past.html
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
language	English
topic	Q Science (General)
spellingShingle	Q Science (General) Ahmad Fuad, Fazia Adyani Walkinshaw, Malcolm D. Fothergill-Gilmore, Linda A. Houston, Dr. Potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches
description	Background & Hypothesis: The parasitic protozoa from the order Trypanosomatida relies exclusively on glycolysis for its survival in the mammalian hosts. As a corollary, the enzymes in this pathway have been recognised as chemotherapeutic targets. Phosphoglycerate mutase (iPGAM), which is the seventh enzyme in the pathway, is of particular interest because it possesses no structural and biochemical relationship with the corresponding enzyme in human. This enzyme has also been validated as an attractive therapeutic target for the treatment of trypanosomatid diseases. The aim of this work is to identify small molecules or compounds that could potentially be developed into potent inhibitors of trypanosomatid iPGAMs through in silico approaches. Methods: In the search for novel inhibitors, a ligand-based virtual screening programme, Ultra Fast Shape Recognition with Atom Types (UFSRAT), was utilised to screen for compounds resembling the substrate/product of iPGAM (3-phosphoglycerate/2phosphoglycerate), before a structure-based approach was applied using AutoDock Vina and COmbining Docking And Similarity Search (CODASS) programmes. The inhibitory effects of selected compounds were subsequently tested by monitoring the oxidation of nicotinamide adenine dinucleotide (NADH) through a continuous coupled assay system. Results: The results revealed that out of this collection of compounds, 7 compounds inhibited iPGAM's activity, with 1 compound from virtual screening analysis exhibited substantial inhibition (14% remaining activity). Discussion & Conclusion: Taken together, the findings from this study indicate that compounds which were discovered through in silico approaches have potentials to be developed as novel drugs that specifically target trypanosomatid iPGAMs.
format	Conference or Workshop Item
author	Ahmad Fuad, Fazia Adyani Walkinshaw, Malcolm D. Fothergill-Gilmore, Linda A. Houston, Dr.
author_facet	Ahmad Fuad, Fazia Adyani Walkinshaw, Malcolm D. Fothergill-Gilmore, Linda A. Houston, Dr.
author_sort	Ahmad Fuad, Fazia Adyani
title	Potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches
title_short	Potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches
title_full	Potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches
title_fullStr	Potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches
title_full_unstemmed	Potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches
title_sort	potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches
publisher	Academy of Medicine, Singapore
publishDate	2015
url	http://irep.iium.edu.my/45423/ http://irep.iium.edu.my/45423/ http://irep.iium.edu.my/45423/1/45423.pdf
first_indexed	2023-09-18T21:04:39Z
last_indexed	2023-09-18T21:04:39Z
_version_	1777410852160274432

Potential novel inhibitors of trypanosomatid phosphoglycerate mutases through ligand-based and structure-based in silico approaches

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