Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Feb 7:18:11779322241230214.
doi: 10.1177/11779322241230214. eCollection 2024.

Computational Studies on 6-Pyruvoyl Tetrahydropterin Synthase (6-PTPS) of Plasmodium falciparum

Shalom N Chinedu  1   2 , Mercy Bella-Omunagbe  1   3 , Esther Okafor  1   4 , Rufus Afolabi  1   4 , Ezekiel Adebiyi  3   4   5   6
Affiliations

Computational Studies on 6-Pyruvoyl Tetrahydropterin Synthase (6-PTPS) of Plasmodium falciparum

Shalom N Chinedu et al. Bioinform Biol Insights. .

Abstract

6-Pyruvoyl tetrahydropterin synthase (6-PTPS) is a lyase involved in the synthesis of tetrahydrobiopterin. In Plasmodium species where dihydroneopterin aldolase (DHNA) is absent, it acts in the folate biosynthetic pathway necessary for the growth and survival of the parasite. The 6-pyruvoyl tetrahydropterin synthase of Plasmodium falciparum (PfPTPS) has been identified as a potential antimalarial drug target. This study identified potential inhibitors of PfPTPS using molecular docking techniques. Molecular docking and virtual screening of 62 compounds including the control to the deposited Protein Data Bank (PDB) structure was carried out using AutoDock Vina in PyRx. Five of the compounds, N,N-dimethyl-N'-[4-oxo-6-(2,2,5-trimethyl-1,3-dioxolan-4-yl)-3H-pteridin-2-yl]methanimidamide (140296439), 2-amino-6-[(1R)-3-cyclohexyl-1-hydroxypropyl]-3H-pteridin-4-one (140296495), 2-(2,3-dihydroxypropyl)-8,9-dihydro-6H-pyrimido[2,1-b]pteridine-7,11-dione (144380406), 2-(dimethylamino)-6-[(2,2-dimethyl-1,3-dioxolan-4-yl)-hydroxymethyl]-3H-pteridin-4-one (135573878), and [1-acetyloxy-1-(2-methyl-4-oxo-3H-pteridin-6-yl)propan-2-yl] acetate (136075207), showed better binding affinity than the control ligand, biopterin (135449517), and were selected and screened. Three conformers of 140296439 with the binding energy of -7.2, -7.1, and -7.0 kcal/mol along with 140296495 were better than the control at -5.7 kcal/mol. In silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies predicted good pharmacokinetic properties of all the compounds while reporting a high risk of irritant toxicity in 140296439 and 144380406. The study highlights the five compounds, 140296439, 140296495, 144380406, 135573878 and 136075207, as potential inhibitors of PfPTPS and possible compounds for antimalarial drug development.

Keywords: Molecular docking; Plasmodium falciparum 6-pyruvoyl tetrahydropterin synthase; antimalarial drugs; drug targets; potential inhibitors.

PubMed Disclaimer

Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
The percentage of amino acids present in PfPTPS. PfPTPS indicates Plasmodium falciparum 6-pyruvoyl tetrahydropterin synthase.
Figure 2.
Figure 2.
The 3D structure of Plasmodium falciparum 6-pyruvoyltetrahydropterin synthase (PDB:1Y13_Chain A). PDB indicates Protein Data Bank.
Figure 3.
Figure 3.
The different poses of compound 140296439; (A)Pose 1, (B)Pose 2, (C) Pose 3.
Figure 4.
Figure 4.
The interactions of the first (A) and second (B) pose of compound 140296439 with the active site of PfPTPS. PfPTPS indicates Plasmodium falciparum 6-pyruvoyl tetrahydropterin synthase.
Figure 5.
Figure 5.
The intermolecular interactions between the active site of PfPTPS and the third pose of compound 140296439 (A) and compound 140296495 (B). PfPTPS indicates Plasmodium falciparum 6-pyruvoyl tetrahydropterin synthase.
Figure 6.
Figure 6.
The intermolecular interactions between the active site of PfPTPS and compound 144380406 (A) and compound 135573878 (B). PfPTPS indicates Plasmodium falciparum 6-pyruvoyl tetrahydropterin synthase.
Figure 7.
Figure 7.
The intermolecular interactions between the active site of PfPTPS and compound 136075207 (A) and the control compound biopterin, 135449517 (B). PfPTPS indicates Plasmodium falciparum 6-pyruvoyl tetrahydropterin synthase.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Kwiatkowski DP. How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet. 2005;77:171-192. doi:10.1086/432519. - DOI - PMC - PubMed
    1. Williams TN, Mwangi TW, Roberts DJ, et al.. An immune basis for malaria protection by the sickle cell trait. PLoS Med. 2005;2:e128-0445. doi:10.1371/JOURNAL.PMED.0020128. - DOI - PMC - PubMed
    1. WHO. World malaria report 2022; 2022. https://www.who.int/teams/global-malaria-programme.
    1. Arrow KJ, Panosian C, Gelband H. Antimalarial drugs and drug resistance. In: Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance. National Academies Press; 2004. https://www.ncbi.nlm.nih.gov/books/NBK215631/. Accessed May 9, 2023. - PubMed
    1. Tse EG, Korsik M, Todd MH. The past, present and future of anti-malarial medicines. Malar J. 2019;18:1-21. doi:10.1186/S12936-019-2724-Z. - DOI - PMC - PubMed

LinkOut - more resources