scholarly journals Remarkable similarity in Plasmodium falciparum and Plasmodium vivax geranylgeranyl diphosphate synthase dynamics and its implication for antimalarial drug design

2018 ◽  
Vol 91 (6) ◽  
pp. 1068-1077 ◽  
Author(s):  
Aishwarya Venkatramani ◽  
Clarisse Gravina Ricci ◽  
Eric Oldfield ◽  
J. Andrew McCammon
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Design ◽  
Plasmodium Vivax ◽  
Antimalarial Drug ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate ◽  
Remarkable Similarity

scholarly journals A specific non-bisphosphonate inhibitor of the bifunctional farnesyl/geranylgeranyl diphosphate synthase in malaria parasites

2017 ◽  
Author(s):  
Jolyn E. Gisselberg ◽  
Zachary Herrera ◽  
Lindsey Orchard ◽  
Manuel Llinás ◽  
Ellen Yeh
Keyword(s):  
Plasmodium Falciparum ◽  
Physicochemical Properties ◽  
Small Molecule ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Drug Targets ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate ◽  
Malaria Parasites ◽  
Starting Point

SummaryIsoprenoid biosynthesis is essential for Plasmodium falciparum (malaria) parasites and contains multiple validated antimalarial drug targets, including a bifunctional farnesyl and geranylgeranyl diphosphate synthase (FPPS/GGPPS). We identified MMV019313 as an inhibitor of PfFPPS/GGPPS. Though PfFPPS/GGPPS is also inhibited by a class of bisphosphonate drugs, MMV019313 has significant advantages for antimalarial drug development. MMV019313 has superior physicochemical properties compared to charged bisphosphonates that have poor bioavailability and strong bone affinity. We also show that it is highly selective for PfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition of PfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes-of-inhibition against PfFPPS/GGPPS. Altogether MMV019313 is the first specific, non-bisphosphonate inhibitor of PfFPPS/GGPPS. Our findings uncover a new small molecule binding site in this important antimalarial drug target and provide a promising starting point for development of Plasmodium-specific FPPS/GGPPS inhibitors.

scholarly journals Re-refinement of Plasmodium falciparum orotidine 5′-monophosphate decarboxylase provides a clearer picture of an important malarial drug target

2018 ◽  
Vol 74 (10) ◽  
pp. 664-668 ◽  
Author(s):  
Walter R. P. Novak ◽  
Korbin H. J. West ◽  
Lucy M. D. Kirkman ◽  
Gabriel S. Brandt
Keyword(s):  
Public Health ◽  
Plasmodium Falciparum ◽  
Drug Design ◽  
Electron Density ◽  
Antimalarial Drug ◽  
Drug Target ◽  
Antimalarial Drugs ◽  
Important Advance ◽  
Structure Based Drug Design ◽  
Monophosphate Decarboxylase

The development of antimalarial drugs remains a public health priority, and the orotidine 5′-monophosphate decarboxylase from Plasmodium falciparum (PfOMPDC) has great potential as a drug target. The crystallization of PfOMPDC with substrate bound represents an important advance for structure-based drug-design efforts [Tokuoka et al. (2008), J. Biochem. 143, 69–78]. The complex of the enzyme bound to the substrate OMP (PDB entry 2za1) would be of particular utility in this regard. However, re-refinement of this structure of the Michaelis complex shows that the bound ligand is the product rather than the substrate. Here, the re-refinement of a set of three structures, the apo enzyme and two versions of the product-bound form (PDB entries 2za1, 2za2 and 2za3), is reported. The improved geometry and fit of these structures to the observed electron density will enhance their utility in antimalarial drug design.

scholarly journals Cloning and characterization of bifunctional enzyme farnesyl diphosphate/geranylgeranyl diphosphate synthase from Plasmodium falciparum

2013 ◽  
Vol 12 (1) ◽  
pp. 184 ◽  
Author(s):  
Fabiana M Jordão ◽  
Heloisa B Gabriel ◽  
João MP Alves ◽  
Claudia B Angeli ◽  
Thaís D Bifano ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Farnesyl Diphosphate ◽  
Bifunctional Enzyme ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate

scholarly journals Triosephosphate isomerase from Plasmodium falciparum:. the crystal structure provides insights into antimalarial drug design

Structure ◽  
1997 ◽  
Vol 5 (6) ◽  
pp. 751-761 ◽  
Author(s):  
Sameer S Velanker ◽  
Soumya S Ray ◽  
Rajesh S Gokhale ◽  
Suma S ◽  
Hemalatha Balaram ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Plasmodium Falciparum ◽  
Drug Design ◽  
Antimalarial Drug ◽  
Triosephosphate Isomerase
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