Abstract
Pyridoxal 5’-phosphate (PLP) functions as a cofactor for hundreds of different enzymes that are crucial to the survival of microorganisms. PLP-dependent enzymes have been extensively characterized and proposed as drug targets in Entamoeba histolytica. This pathogen is unable to synthesize vitamin B6 via de-novo pathway and relies on the uptake of vitamin B6 vitamers from the host which are then phosphorylated by the enzyme pyridoxal kinase to produce PLP, the active form of vitamin B6. Previous studies from our lab shows that EhPLK is essential for the survival and growth of this protozoan parasite and its active site differs significantly with respect to its human homologue making it a potential drug target. In-silico screening of EhPLK against small molecule libraries were performed and top five ranked molecules were shortlisted on the basis of docking scores. These compounds dock into the PLP binding site of the enzyme such that binding of these compounds hinders the binding of substrate. Of these five compounds, two compounds showed inhibitory activity with IC50 values between 100-250 μM when tested in-vitro. The effect of these compounds proved to be extremely lethal for Entamoeba trophozoites in cultured cells as the growth was hampered by 91.5% and 89.5% when grown in the presence of these compounds over the period of 72 hours.
Highlights
Amoebiasis is one of the most widespread and a global intestinal parasitic disease caused by Entamoeba histolytica (Walsh, 1986)
EhPLK is a promising drug target which is critical for the survival of E. histolytica
Inhibitors tested against EhPLK, namely ZINC26710739 and ZINC26710858, have shown encouraging results in inhibiting the growth of E. histolytica cultured cells
Summary
Amoebiasis is one of the most widespread and a global intestinal parasitic disease caused by Entamoeba histolytica (Walsh, 1986). It is a causative agent of amoebic dysentery leading to nearly 100,000 deaths and 35 to 50 million new infections per year across the globe (Li and Stanley, 1996; Petri et al, 2000; Stauffer and Ravdin, 2003; Bercu et al, 2007). PLP in E. histolytica is produced by EhPLK by salvage pathway. PLP is the most active form of vitamin B6 (Gyorgy, 1956), which serves as a cofactor for various enzymes associated with racemization, transamination, decarboxylation and replacement reactions (Percudani and Peracchi, 2003). Enzymes of the sulfur metabolism pathway such as O-acetylserine sulfhydrylase contain PLP
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
