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

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.

PDF - Published Version Restricted to Repository staff only Download (483kB) | Request a copy

Abstract

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.

Item Type:	Conference or Workshop Item (Poster)
Additional Information:	7200/45423
Uncontrolled Keywords:	Trypanosomatid Phosphoglycerate Mutases
Subjects:	Q Science > Q Science (General)
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Engineering > Department of Biotechnology Engineering
Depositing User:	Dr Fazia Adyani Ahmad Fuad
Date Deposited:	04 Nov 2015 11:46
Last Modified:	27 Dec 2017 10:19
URI:	http://irep.iium.edu.my/id/eprint/45423

Actions (login required)

View Item