The Role of Fragment‐based Discovery in Lead Finding

Hubbard, Roderick E.

doi:10.1002/9783527683604.ch01

Cited by 11 publications

(9 citation statements)

References 111 publications

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“…It is then important to optimize the features of the fragment that are making the key interaction with the target binding site, before embarking on large-scale optimization of druglike properties. The second feature is that fragments can provide a diversity of start points for optimization. , In this study, the zinc-chelating groups of the glycine and imidazole series bind so that the remainder of the compound provides different vectors and opportunities for reaching into the linker and tunnel regions, reflected in the different amino acid groups that are contacted.…”

Section: Resultsmentioning

confidence: 99%

Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity

et al. 2020

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UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 μg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.

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Section: Resultsmentioning

confidence: 99%

Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity

et al. 2020

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“…In FBDD, a library of small molecules, called fragments, are screened to identify ones that bind to biological targets of interest. The bound fragments are further optimized to generate pharmaceutical candidates . The assay published in 2017 was only applicable to positively charged molecules that could be detected by UV–vis .…”

Section: Mobility Shift Acementioning

confidence: 99%

Affinity Capillary Electrophoresis: A Critical Review of the Literature from 2018 to 2020

et al. 2020

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“…Unlike a fragment‐based approach, however, the novel scaffold methodology does not build from a known target site, typically lacks a bioactivity and thus is a more of a de novo approach. Another contrasting feature is that, for fragment‐based methodology, fragments are screened first, selected and then systematically elaborated into lead structures . In a novel scaffold‐based approach, the fragment or scaffold is empirically selected, elaborated into sets or libraries of target molecules and then screened for whole plant or whole organism activity.…”

Section: Bioactive Hypothesismentioning

confidence: 99%

“…Another contrasting feature is that, for fragment-based methodology, fragments are screened first, selected and then systematically elaborated into lead structures. 20 In a novel scaffold-based approach, the fragment or scaffold is empirically selected, elaborated into sets or libraries of target molecules and then screened for whole plant or whole organism activity. A schematic comparing both approaches is depicted in Fig.…”

Section: Definition and Various Approachesmentioning

confidence: 99%

Lead generation in crop protection research: a portfolio approach to agrochemical discovery

Garizi¹,

Hegde²,

Hunter³

et al. 2016

Pest Management Science

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The need for increased food and feed supply to support future global demand with the added challenges of resistance pressure and an evolving regulatory environment necessitates the discovery of new crop protection agents for growers of today and tomorrow. Lead generation is the critical 'engine' for maintaining a robust pipeline of new high-value products. A wide variety of approaches exist for the generation of new leads, many of which have demonstrated success. Each approach features some degree of merit or benefit while also having some inherent drawback or level of risk. While risk for any single approach can be mitigated in a variety of different ways depending on the approach, long-term viability of a successful lead generation program merits utilization of a portfolio of different approaches and methodologies for the generation of new leads. © 2016 Society of Chemical Industry.

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The Role of Fragment‐based Discovery in Lead Finding

Cited by 11 publications

References 111 publications

Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity

Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity

Affinity Capillary Electrophoresis: A Critical Review of the Literature from 2018 to 2020

Lead generation in crop protection research: a portfolio approach to agrochemical discovery

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