Binding of Quinoline-Based Inhibitors to &amp;lt;i&amp;gt;Plasmodium falciparum&amp;lt;/i&amp;gt; Lactate Dehydrogenase: A Molecular Docking Study

Victor F Waingeh,Adam T Groves,Jeremy A Eberle

doi:10.4236/ojbiphy.2013.34034

Abstract

Development of new antimalarial drugs continues to be of great importance due to the resistance of the malaria parasite to currently used drugs. Glycolytic enzymes have emerged as potential targets for the development of new drugs due to the reliance of the parasite on glycolysis for energy. In this study, molecular docking was used to study the binding of some quinoline-based drugs to the glycolytic enzyme lactate dehydrogenase. The docking studies identified two potential binding sites for each ligand, one of them being the cofactor-binding site. For all ligands studied, there was the comparable binding to the cofactor-binding site as well as the secondary binding site when the cofactor was absent. All ligands showed significantly lower binding affinity than NADH for the cofactor binding site. The alternative site was the site of preference when docking was done in the presence of the cofactor. While binding to the cofactor site may support other studies suggesting potential for competitive inhibition, the fact that the binding affinities of all the ligands are significantly lower than that for NADH in this site suggests that these ligands will be ineffective competitive inhibitors. The identification of an alternative binding site with comparable affinity that is not affected by the presence of the cofactor may suggest the possibility of non-competitive inhibition that requires further exploration.

Highlights

Malaria is a major infectious disease that kills millions of people worldwide yearly, with the majority of fatalities occurring in poor countries
All four ligands were successfully docked to P. falciparum lactate dehydrogenase (pfLDH)
Molecular docking was used to study the binding of four quinolone-based ligands to Plasmodium falciparum lactate dehydrogenase

Summary

Introduction

Malaria is a major infectious disease that kills millions of people worldwide yearly, with the majority of fatalities occurring in poor countries. Plasmodium falciparum (P. falciparum) is the most virulent of the malaria parasites and its resistance to currently available drugs continues to grow, and presents an impediment to attempts to successfully deal with the disease. There is, great need and challenge to continuously develop new inhibitors, with the goal to overcome parasite resistance. Chloroquine and other quinoline-based compounds such as quinine, mefloquine and amodiaquine (Figure 1) have been used for the treatment of malaria incidents for a long time. The mechanism by which these compounds exert their anti-malarial properties is still not fully evident. Growing and spreading resistance to these current drugs is of concern and emphasizes the need for continuous work aiming at developing new and better anti-malarials

Methods

Results

Conclusion