A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters

Nikiforov, P.O.; Surade, Sachin; Błaszczyk, M.; Delorme, Vincent; Brodin, Priscille; Baulard, Alain R.; Blundell, Tom L.; Abell, C.

doi:10.1039/c5ob02630j

Cited by 42 publications

(48 citation statements)

References 18 publications

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“…In such cases the overlapping parts form a nucleus where dissimilar parts come together. In a recent example, a gain of 2 orders of magnitude in potency was achieved for an inhibitor of flavindependent monooxygenase (EthA) transcriptional repressor (EthR) (Nikiforov et al, 2016) where the existence of overlapping groups within fragments bound to EthR allowed the use of merging as an optimization strategy.…”

Section: Mergingmentioning

confidence: 99%

In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery

et al. 2020

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Section: Mergingmentioning

confidence: 99%

In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery

et al. 2020

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“…Our group has previously employed DSF to screen a 1250 member fragment library against EthR, with fragments showing Δ T m ≥1 °C at 10 m m concentration being classed as hits . Fragment‐merging and ‐linking strategies subsequently generated improved analogues with low‐micromolar IC 50 values against the EthR–DNA interaction …”

Section: Figurementioning

confidence: 99%

“…The eleven fragments that appeared as hits in at least one of the primary assays were passed to the fragment validation stage, which was performed using SPR as previously described . In the SPR assay, the ability of compounds to disrupt the binding of EthR to a biotinylated 106 bp DNA sequence (DNA 106 ) encompassing the operator region was measured.…”

Section: Figurementioning

confidence: 99%

Fragment Screening against the EthR–DNA Interaction by Native Mass Spectrometry

et al. 2017

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Native nanoelectrospray ionization mass spectrometry is an underutilized technique for fragment screening. In this study, the first demonstration is provided of the use of native mass spectrometry for screening fragments against a protein–DNA interaction. EthR is a transcriptional repressor of EthA expression in Mycobacterium tuberculosis (Mtb) that reduces the efficacy of ethionamide, a second‐line antitubercular drug used to combat multidrug‐resistant Mtb strains. A small‐scale fragment screening campaign was conducted against the EthR–DNA interaction using native mass spectrometry, and the results were compared with those from differential scanning fluorimetry, a commonly used primary screening technique. Hits were validated by surface plasmon resonance and X‐ray crystallography. The screening campaign identified two new fragments that disrupt the EthR–DNA interaction in vitro (IC50=460–610 μm) and bind to the hydrophobic channel of the EthR dimer.

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“…C . Merging example towards the development of small molecule inhibitors of Mycobacterium tuberculosis transcriptional repressor protein (EthR) …”

Section: Introductionmentioning

confidence: 99%

Chemistry‐driven Hit‐to‐lead Optimization Guided by Structure‐based Approaches

Hoffer

Muller

Roché

et al. 2018

Molecular Informatics

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For several decades, hit identification for drug discovery has been facilitated by developments in both fragment-based and high-throughput screening technologies. However, a major bottleneck in drug discovery projects continues to be the optimization of primary hits from screening campaigns in order to derive lead compounds. Computational chemistry or molecular modeling can play an important role during this hit-to-lead (H2L) stage by both suggesting putative optimizations and decreasing the number of compounds to be experimentally synthesized and evaluated. However, it is also crucial to consider the feasibility of organically synthesizing these virtually designed compounds. Furthermore, the generated molecules should have reasonable physicochemical properties and be medicinally relevant. This review focuses on chemistry-driven and structure-based computational methods that can be used to tackle the difficult problem of H2L optimization, with emphasis being placed on the strategy developed in our laboratory.

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A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters

Abstract: With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic.

Cited by 42 publications

References 18 publications

In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery

In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery

Fragment Screening against the EthR–DNA Interaction by Native Mass Spectrometry

Chemistry‐driven Hit‐to‐lead Optimization Guided by Structure‐based Approaches

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