Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening

Zhu, Di; Johannsen, Sandra; Masini, Tiziana; Simonin, Céline; Haupenthal, Jörg; Illarionov, Boris; Andreas, Anastasia; Awale, Mahendra; Gierse, Robin M.; Laan, Tridia van der; Vlag, Ramon van der; Nasti, Rita; Poizat, Mael; Reiling, Norbert; Müller, Rolf; Fischer, Markus; Reymond, Jean‐Louis; Hirsch, Anna K. H.

doi:10.1039/d2sc02371g

Cited by 13 publications

(26 citation statements)

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“…8 A common strategy in designing inhibitors of TPP-dependent enzymes lies in the use of TPP analogues. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] These mostly feature a central neutral ring in place of the thiazolium ring of TPP, e.g. deazathiamine pyrophosphate 3 18 (deazaTPP), triazole-TPP 4 19 and furan-TPP 5 20 (Fig.…”

Section: Introductionmentioning

confidence: 99%

Furan-based inhibitors of pyruvate dehydrogenase: SAR study, biochemical evaluation and computational analysis

Chan

Parle

et al. 2023

Org. Biomol. Chem.

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Section: Introductionmentioning

confidence: 99%

Furan-based inhibitors of pyruvate dehydrogenase: SAR study, biochemical evaluation and computational analysis

Chan

Parle

et al. 2023

Org. Biomol. Chem.

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“…In our previous work, we used ligand-based virtual screening (LBVS) as a powerful tool to identify new inhibitors based on known reference compounds for the target of interest . LBVS relies solely on the use of descriptors of molecular structures and properties to compare various molecules and does not require crystallographic data .…”

Section: Resultsmentioning

confidence: 99%

“…Compound 10, where in comparison to 2 a NH 2 − is replacing a hydroxyl group, is the most active oxime against P. falciparum with an IC 50 value of 38 ± 2 μM. Although we increased the activity 2-fold with compound 10, replacing the oxime moiety with an imine (11) or a hydrazone (12) improves activity. Replacing the oxime with an alcohol group (13) leads to a ten-fold increase (IC 50 = 10 ± 2 μM) in comparison to the parent compound 2.…”

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confidence: 85%

High Target Homology Does Not Guarantee Inhibition: Aminothiazoles Emerge as Inhibitors of Plasmodium falciparum

Johannsen,

Gierse,

Krüger

et al. 2024

ACS Infect. Dis.

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In this study, we identified three novel compound classes with potent activity against Plasmodium falciparum, the most dangerous human malarial parasite. Resistance of this pathogen to known drugs is increasing, and compounds with different modes of action are urgently needed. One promising drug target is the enzyme 1-deoxy-D-xylulose-5phosphate synthase (DXPS) of the methylerythritol 4-phosphate (MEP) pathway for which we have previously identified three active compound classes against Mycobacterium tuberculosis. The close structural similarities of the active sites of the DXPS enzymes of P. falciparum and M. tuberculosis prompted investigation of their antiparasitic action, all classes display good cell-based activity. Through structure−activity relationship studies, we increased their antimalarial potency and two classes also show good metabolic stability and low toxicity against human liver cells. The most active compound 1 inhibits the growth of blood-stage P. falciparum with an IC 50 of 600 nM. The results from three different methods for target validation of compound 1 suggest no engagement of DXPS. All inhibitor classes are active against chloroquine-resistant strains, confirming a new mode of action that has to be further investigated.

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“…63,64 As DXPS is essential to many pathogenic microorganisms, but is absent in mammals, there has been considerable interest in targeting DXPS as an antimicrobial strategy in recent years. [10][11][12][13]56 To gain structural insights to aid ligand development, we recently solved some crystal structures of DXPS from Klebsiella pneumoniae. 65 In this work, we obtained an X-ray crystal structure of the binary complex between the KpDXPS and 8b.…”

Section: Rational Functionalisation Of the Central Ring Improves Sele...mentioning

confidence: 99%

Strategies on Designing Thiamine Analogues for Inhibition of Thiamine Diphosphate (ThDP)-dependent Enzymes: Systematic Investigation through Scaffold Switching and C2-Functionalisation

Chan

Irfan

et al. 2023

Preprint

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Thiamine diphosphate (ThDP), the bioactive form of vitamin B1, is an essential coenzyme needed for processes of cellular metabolism in all organisms. ThDP-dependent enzymes all require ThDP as a coenzyme for catalytic activity, although individual enzymes vary significantly in substrate preferences and biochemical reactions. A popular way to study the role of these enzymes through chemical inhibition is to use thiamine/ThDP analogues, which typically feature a neutral aromatic ring in place of the positive thiazolium ring of ThDP. While ThDP analogues have aided work in understanding the structural and mechanistic aspects of the enzyme family, at least two key questions regarding the ligand design strategy remain unresolved: 1) among the reported aromatic rings, which is the best? and 2) how can we achieve selectivity towards a given ThDP-dependent enzyme? In this work, we synthesise derivatives of these analogues covering all central aromatic rings used in the past decade and make a head-to-head comparison of all the compounds as inhibitors of several ThDP-dependent enzymes. Thus, we establish the relationship between the nature of the central ring and the inhibitory profile of these ThDP-competitive enzyme inhibitors. We also demonstrate that introducing a C2-substituent onto the central ring to explore the unique substrate-binding pocket can improve selectivity.

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Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening

Abstract: In the present manuscript, we describe how we successfully used ligand-based virtual screening (LBVS) to identify two small-molecule, drug-like hit classes with excellent ADMET profiles against the difficult to address...

Cited by 13 publications

References 61 publications

Furan-based inhibitors of pyruvate dehydrogenase: SAR study, biochemical evaluation and computational analysis

Furan-based inhibitors of pyruvate dehydrogenase: SAR study, biochemical evaluation and computational analysis

High Target Homology Does Not Guarantee Inhibition: Aminothiazoles Emerge as Inhibitors of Plasmodium falciparum

Strategies on Designing Thiamine Analogues for Inhibition of Thiamine Diphosphate (ThDP)-dependent Enzymes: Systematic Investigation through Scaffold Switching and C2-Functionalisation

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