Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of <i>Mycobacterium tuberculosis</i> InhA

Encinas, Lourdes; O’Keefe, Heather; Neu, Margarete; Remuiñán, Modesto J.; Patel, Amish; Guardia, A.C.; Davie, Christopher P.; Pérez-Macías, Natalia; Yang, Hongfang; Convery, M.A.; Messer, Jeffrey A.; Pérez-Herrán, Esther; Centrella, Paolo A.; Álvarez-Gómez, Daniel; Clark, Matthew; Huss, Sophie; O’Donovan, Gary; Ortega-Muro, Fátima; McDowell, William; Castañeda, Pablo; Arico-Muendel, Christopher C.; Pajk, Stane; Rullás, Joaquín; Angulo-Barturen, Íñigo; Álvarez-Ruíz, Emilio; Mendoza-Losana, Alfonso; Ballell, Lluís; Castro-Pichel, Julia; Evindar, Ghotas

doi:10.1021/jm401326j

Cited by 111 publications

(105 citation statements)

References 39 publications

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“…Series 10 was the only NAD + -dependent series explored. In contrast to previous reports of cell-based activity for NADH-dependent compounds (13), the parent compound of the series 10, compound 10a, had an MIC of 12 μM, equivalent to the two most potent compounds from NADH-dependent series reported herein, demonstrating that bactericidal compounds can bind to either reduced or oxidized cofactor-bound forms of InhA. This result suggests that further efforts to identify InhA inhibitors that bind specifically to the NAD + -bound form of the enzyme could yield bactericidal compounds.…”

Section: Significancecontrasting

confidence: 77%

Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology

Soutter¹,

Centrella²,

Clark

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Millions of individuals are infected with and die from tuberculosis (TB) each year, and multidrug-resistant (MDR) strains of TB are increasingly prevalent. As such, there is an urgent need to identify novel drugs to treat TB infections. Current frontline therapies include the drug isoniazid, which inhibits the essential NADH-dependent enoyl–acyl-carrier protein (ACP) reductase, InhA. To inhibit InhA, isoniazid must be activated by the catalase-peroxidase KatG. Isoniazid resistance is linked primarily to mutations in the katG gene. Discovery of InhA inhibitors that do not require KatG activation is crucial to combat MDR TB. Multiple discovery efforts have been made against InhA in recent years. Until recently, despite achieving high potency against the enzyme, these efforts have been thwarted by lack of cellular activity. We describe here the use of DNA-encoded X-Chem (DEX) screening, combined with selection of appropriate physical properties, to identify multiple classes of InhA inhibitors with cell-based activity. The utilization of DEX screening allowed the interrogation of very large compound libraries (1011 unique small molecules) against multiple forms of the InhA enzyme in a multiplexed format. Comparison of the enriched library members across various screening conditions allowed the identification of cofactor-specific inhibitors of InhA that do not require activation by KatG, many of which had bactericidal activity in cell-based assays.

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Section: Significancecontrasting

confidence: 77%

Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology

Soutter¹,

Centrella²,

Clark

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Since InhA is a flexible enzyme which contains a substrate-binding loop that samples multiple distinct conformations when it forms a lid on the active site, [49] several conformations of InhA from multiple chains of four different ligand-bound crystal structures of InhA were utilized as targets for these docking studies. 2X23 [50] and 3FNH [32] are both bound to triclosan derivatives, while 4COD [37] and 4BQP [38] are new crystal structures of InhA bound to structurally distinct lead compounds from GlaxoSmithKline and AstraZeneca, respectively. To help validate the modeling protocols, positive control docking calculations were performed.…”

Section: Resultsmentioning

confidence: 99%

“…[54] They were minimized in Avogadro using the MMFF94s force field, first by steepest descent, followed by the conjugate gradient method. The X-ray crystal structures of the targets were obtained from the RCSB Protein Data Bank [55] , PDB codes: 2X23 [50] , 3FNH [32] , 4COD [37] , and 4BQP. [38] Hydrogen atoms were added to the models of the targets using the MolProbity server.…”

Section: Methodsmentioning

confidence: 99%

“…[29] Subsequent modifications of the TRC scaffold led to the synthesis of a wide range of direct inhibitors of this enzyme. [30-32] Additionally, molecules belonging to the class of pyrrolidine carboxamides, [33] isoniazid-NAD adducts, [34] 2,4- diaryloxazolones, [35] triazoles, [36] proline amides (GSK) [37] and thiazoles (AZ) [38] have been reported to effectively inhibit InhA. In our efforts to discover direct and effective inhibitors of the bacterial and parasitic enoyl-acyl reductases, we designed and synthesized a broad range of TRC analogs.…”

Section: Introductionmentioning

confidence: 99%

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Biological Evaluation of Potent Triclosan‐Derived Inhibitors of the Enoyl–Acyl Carrier Protein Reductase InhA in Drug‐Sensitive and Drug‐Resistant Strains of Mycobacterium tuberculosis

Stec

Vilchèze

Lun³

et al. 2014

ChemMedChem

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New triclosan (TRC) analogs were evaluated for their activity against the enoyl-acyl carrier protein reductase InhA in Mycobacterium tuberculosis (Mtb). TRC is a well-known inhibitor of InhA and specific modifications to its positions 5 and 4′ afforded twenty-seven derivatives; of these compounds seven derivatives showed an improved potency in comparison to TRC. These analogs were active against both drug-susceptible and drug-resistant Mtb strains. The most active compound in this series, 3, had an MIC value of 0.6 μg/mL (1.5 μM) against wild-type Mtb. At a concentration equal to its MIC, this molecule inhibited the purified InhA enzyme to the extent of 98%, and it showed an IC50 value of 90 nM. Compounds 3 and 14 were able to inhibit the biosynthesis of mycolic acids. Furthermore, mc24914, an Mtb strain overexpressing inhA, was resistant to the compounds 3 and 14, supporting the notion that InhA is the likely molecular target of the TRC derivatives presented herein.

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“…Based on the methylthiazole compounds discovered at GSK (Ballell Pages et al 2010;Castro Pichel et al 2012), scientists at AstraZeneca have published their investigation of the binding mode of these agents to InhA (Shirude et al 2013). This is part of an effort to discover direct InhA inhibitors that, unlike isoniazid, do not require activation by KatG (Encinas et al 2014). Defective KatG activation is the dominant resistance determinant in isoniazid-resistant Mtb clinical isolates.…”

Section: Mechanism-and Structure-based Drug Designmentioning

confidence: 99%

The Tuberculosis Drug Discovery and Development Pipeline and Emerging Drug Targets

Mdluli

Kaneko

Upton

2015

Cold Spring Harbor Perspectives in Medicine

134

115

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The recent accelerated approval for use in extensively drug-resistant and multidrug-resistanttuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal. INTRODUCTION AND CURRENT DRUG DEVELOPMENT PIPELINE

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Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of Mycobacterium tuberculosis InhA

Cited by 111 publications

References 39 publications

Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology

Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology

Biological Evaluation of Potent Triclosan‐Derived Inhibitors of the Enoyl–Acyl Carrier Protein Reductase InhA in Drug‐Sensitive and Drug‐Resistant Strains of Mycobacterium tuberculosis

The Tuberculosis Drug Discovery and Development Pipeline and Emerging Drug Targets

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