Potential inhibitors of the glycolytic enzymes from Plasmodium knowlesi identified by virtual screening analysis

Ogu Salim, Nurhainis and Zulrimi, Nurzati Amani and Ahmad Fuad, Fazia Adyani (2016) Potential inhibitors of the glycolytic enzymes from Plasmodium knowlesi identified by virtual screening analysis. In: International Conference of Biotechnology Engineering (ICBioE2016), 25-27 July 2016, Kuala Lumpur.

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Abstract

Malaria remains pandemic globally and continues to threaten half of the current world’s population. In Malaysia, most malaria-related cases are now caused by Plasmodium knowlesi, an emerging zoonotic monkeyborne parasite, which is potentially fatal if remains untreated. Improved strategy in drug discovery is extremely important due to the development of parasite’s resistance towards the current antimalarial drugs. Since the glycolytic pathway is essential for parasite’s survival, the enzymes involved in this pathway, including hexokinase (Pk-HK) and lactate dehydrogenase (Pk-LDH), are regarded as attractive drug targets. This study aims to screen for small molecule compounds which may potentially be developed into potent drugs that specifically target these two enzymes. Virtual screening analyses comprising of structure and ligand-based screens were conducted to search for potential novel inhibitors of both enzymes. By using MODELLER, a comparative protein structure modeling programme, the model of Pk-HK and Pk-LDH have been generated based on hexokinase from Schistosoma mansoni (Sm-HK) and lactate dehydrogenase from Plasmodium falciparum (Pf-LDH), with 33% and 91% sequence similarity respectively. By using this model, docking and scoring functions through Ligand Discovery at Edinburgh UniverSity (LIDAEUS), a structurebased approach, were conducted and yielded more than 200 binding candidates for Pk-HK. The binding affinity scores for the best ten ligands docked to Pk-HK are in the range of -83 kcal/mol to -93 kcal/mol. Through ligand-based approach using Ultra-Fast Shape Recognition with Atom Types (UFSRAT), another 200 compound similar to glucose and oxamate were discovered, where the majority displays great similarity to glucose with similarity score (Sqc) of more than 0.5. This study has successfully discovered potential inhibitors of these two glycolytic enzymes from P.knowlesi, however further validation through suitable inhibition assay system has yet to be conducted.

Item Type:	Conference or Workshop Item (Slide Presentation)
Subjects:	Q Science > Q Science (General) Q Science > QD Chemistry
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:	10 Mar 2022 11:50
Last Modified:	17 Mar 2022 16:59
URI:	http://irep.iium.edu.my/id/eprint/97135

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