Virtual screening reveals allosteric inhibitors of the Toxoplasma gondii thymidylate synthase–dihydrofolate reductase

Sharma, Hitesh Kumar; Landau, Mark J.; Sullivan, T. E.; Kumar, Vidya P.; Dahlgren, Markus; Jorgensen, William L.; Anderson, Karen S.

doi:10.1016/j.bmcl.2013.12.039

Cited by 9 publications

(8 citation statements)

References 33 publications

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“…The ligands were prepared using Maestro’s Ligprep utility, and Epik software 37 was used to generate protonation states at the target pH (7.0 ± 2.0). 38 The protein structure of IGPS was obtained from the Protein Data Bank (PDB entry 1GPW), the crystal structure of the enzyme complex from T. maritima . The position of PRFAR in the HisF active site was determined after superimposing the phosphate groups in the T. maritima IGPS crystal and the PRFAR-bound complex in the yeast enzyme (PDB entry 1OX5).…”

Section: Methodsmentioning

confidence: 99%

Allosteric Communication Disrupted by a Small Molecule Binding to the Imidazole Glycerol Phosphate Synthase Protein–Protein Interface

Rivalta

Lisi²,

Snoeberger³

et al. 2016

Biochemistry

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Allosteric enzymes regulate a wide range of catalytic transformations, including biosynthetic mechanisms of important human pathogens, upon binding of substrate molecules to an orthosteric (or active) site and effector ligands at distant (allosteric) sites. We find that enzymatic activity can be impaired by small molecules that bind along the allosteric pathway connecting the orthosteric and allosteric sites, without competing with endogenous ligands. Noncompetitive allosteric inhibitors disrupted allostery in the imidazole glycerol phosphate synthase (IGPS) enzyme from Thermotoga maritima as evidenced by nuclear magnetic resonance, microsecond time-scale molecular dynamics simulations, isothermal titration calorimetry, and kinetic assays. The findings are particularly relevant for the development of allosteric antibiotics, herbicides, and antifungal compounds because IGPS is absent in mammals but provides an entry point to fundamental biosynthetic pathways in plants, fungi, and bacteria. Graphical abstract *Corresponding Authors: ivan.rivalta@ens-lyon.fr.,

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Section: Methodsmentioning

confidence: 99%

Allosteric Communication Disrupted by a Small Molecule Binding to the Imidazole Glycerol Phosphate Synthase Protein–Protein Interface

Rivalta

Lisi²,

Snoeberger³

et al. 2016

Biochemistry

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“…These compounds include glutaric acid (2), N-(4-carboxyphenyl) succinamic acid (3), diglycolic anhydride (4), (R)-4-((1-cyclopropylethyl) (phenyl)amino)-4-oxobutanoic acid, (E)-4-((2-(methoxycarbonyl)-4-methythiophen-3-yl)amino)-4-oxobut-2-enoic acid, and 3,4-dihydro-2H-benzo [b][ 1 , 4 ]dioxepine-7-carboxylic acid, in addition to the previously reported diphosphonate PDPA referred to, in the current study, by compound (1) [ 13 , 21 ]. Previous studies on PDPA reported that its binding to hTS was able to cause significant inhibition of its activity, and stabilize loop 181–197 in an inactive conformation [ 22 , 23 ]. In the present investigation, PDPA exhibited higher selectivity for inhibition of native hTS relative to active-stabilized R163K-hTS.…”

Section: Discussionmentioning

confidence: 99%

Biomolecular study of human thymidylate synthase conformer-selective inhibitors: New chemotherapeutic approach

et al. 2018

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Thymidylate synthase (TS) is a well-validated target for the therapy of adult cancers. Propane-1,3-diphosphonic acid (PDPA) has significant inhibitory properties against human thymidylate synthase (hTS) relative to mouse TS which is not predicted to adopt an inactive conformer. The current research aims to identify novel, lead inhibitors of hTS and examine the prediction that they bind selectively to hTS enzymes existing in different conformational equilibria. Conformer-selectivity was evaluated through performing activity inhibition studies, as well as intrinsic fluorescence (IF) studies in comparison to the known orthosteric inhibitor raltitrexed (RTX). Human TS was isolated from recombinant bacteria expressing either native hTS, capable of conformational switching, or an actively stabilized mutant (R163K-hTS). The examined test compounds were rationally or virtually predicted to have inhibitory activity against hTS. Among these compounds, glutarate, N-(4-carboxyphenyl) succinamic acid, and diglycolic anhydride showed higher selectivity towards native hTS as compared to R163K-hTS. The active site inhibitor RTX showed significantly higher inhibition of R163K-hTS relative to hTS. Targeting hTS via conformational selectivity represents a future approach for overcoming reported resistance towards active-state TS analogs.

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“…Cheminformaticsbased virtual screens are being performed to identify novel antiToxoplasma compounds (87,124,125). The availability of crystal structures for some of the T. gondii proteins and the improvement in computational molecular modeling approaches facilitate this approach.…”

Section: Compounds Identified In Screensmentioning

confidence: 99%

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

McFarland

Zach

Wang

et al. 2016

Antimicrob Agents Chemother

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Toxoplasma gondii is a ubiquitous apicomplexan parasite capable of infecting humans and other animals. Current treatment options for T. gondii infection are limited and most have drawbacks, including high toxicity and low tolerability. Additionally, no FDA-approved treatments are available for pregnant women, a high-risk population due to transplacental infection. Therefore, the development of novel treatment options is needed. To aid this effort, this review highlights experimental compounds that, at a minimum, demonstrate inhibition of in vitro growth of T. gondii. When available, host cell toxicity and in vivo data are also discussed. The purpose of this review is to facilitate additional development of anti-Toxoplasma compounds and potentially to extend our knowledge of the parasite.

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Virtual screening reveals allosteric inhibitors of the Toxoplasma gondii thymidylate synthase–dihydrofolate reductase

Cited by 9 publications

References 33 publications

Allosteric Communication Disrupted by a Small Molecule Binding to the Imidazole Glycerol Phosphate Synthase Protein–Protein Interface

Allosteric Communication Disrupted by a Small Molecule Binding to the Imidazole Glycerol Phosphate Synthase Protein–Protein Interface

Biomolecular study of human thymidylate synthase conformer-selective inhibitors: New chemotherapeutic approach

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

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