Current perspectives in fragment-based lead discovery (FBLD)

Lamoree, Bas; Hubbard, Roderick E.

doi:10.1042/ebc20170028

Cited by 139 publications

(145 citation statements)

References 58 publications

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“…What distinguishes fragment-based approaches from other smallmolecule HTS assays is the further fine-tuning of small-molecule screens. Once fragments are identified as binders of the target protein, researchers conduct medicinal chemistry to grow, ligate and merge the fragments into potent and selective inhibitors (Erlanson, 2012;Lamoree & Hubbard, 2017) (Fig. 3b).…”

Section: Fragment-based Drug Discovery Of Potent and Specific Usp7 Inmentioning

confidence: 99%

“…The researchers that developed the allosteric USP7 inhibitors followed up with a study in which they described in detail the fragment-based medicinal chemistry approach to identify novel USP7 inhibitors (O'Dowd et al, 2018). This study demonstrated that employing SPR, a commonly used technology to detect binding (Erlanson, 2012), can be first used to identify potential allosteric binders of the protein, before continuing with X-ray crystallography to enable structure-based design (O'Dowd et al, 2018), an approach that has been responsible for many drugs developed to date (Erlanson, 2012;Lamoree & Hubbard, 2017). With both studies, the authors showed that structure-based design can aid with the elucidation of the mechanisms of action of novel inhibitors and can provide new insights into the functions of complex proteins with additional regulatory sites beyond the active site.…”

Section: Fragment-based Drug Discovery Of Potent and Specific Usp7 Inmentioning

confidence: 99%

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Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Veggiani

Gerpe

Sidhu

et al. 2019

Pharmacology & Therapeutics

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a b s t r a c t a r t i c l e i n f o Development of effective cancer therapeutic strategies relies on our ability to interfere with cellular processes that are dysregulated in tumors. Given the essential role of the ubiquitin proteasome system (UPS) in regulating a myriad of cellular processes, it is not surprising that malfunction of UPS components is implicated in numerous human diseases, including many types of cancer. The clinical success of proteasome inhibitors in treating multiple myeloma has further stimulated enthusiasm for targeting UPS proteins for pharmacological intervention in cancer treatment, particularly in the precision medicine era. Unfortunately, despite tremendous efforts, the paucity of potent and selective UPS inhibitors has severely hampered attempts to exploit the UPS for therapeutic benefits. To tackle this problem, many groups have been working on technology advancement to rapidly and effectively screen for potent and specific UPS modulators as intracellular probes or early-phase therapeutic agents. Here, we review several emerging technologies for developing chemical-and protein-based molecules to manipulate UPS enzymatic activity, with the aim of providing an overview of strategies available to target ubiquitination for cancer therapy.

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Section: Fragment-based Drug Discovery Of Potent and Specific Usp7 Inmentioning

confidence: 99%

Section: Fragment-based Drug Discovery Of Potent and Specific Usp7 Inmentioning

confidence: 99%

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Veggiani

Gerpe

Sidhu

et al. 2019

Pharmacology & Therapeutics

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“…Overall, the FBDD screening approach includes: (1) fragment library, (2) target enablement, (3) screening chemical fragments with biophysical or biochemical assays to identify fragment hits, (4) generation of fragment-binding model by biophysical characterization and structure determination, and (5) fragment to lead drug-like compound optimization through medicinal chemistry and further characterization of the fragment. 200 Early on, fragment linking studies identified novel small-molecule ligands for ribosomal antibiotic binding sites. 201 A benzimidazole hit fragment for an internal loop within domain II of the HCV IRES was used to grow a set of ligands with binding affinity in the micromolar range.…”

Section: Fragment-based Drug Discovery (Fbdd)mentioning

confidence: 99%

Unveiling the druggable RNA targets and small molecule therapeutics

Sztuba-Solińska

Chávez-Calvillo

Cline

2019

Bioorganic & Medicinal Chemistry

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Keywords:RNA structure and function RNA interactions Epitranscriptomics Small molecules RNA-based therapeutics RNA in disease Drug target A B S T R A C T The increasing appreciation for the crucial roles of RNAs in infectious and non-infectious human diseases makes them attractive therapeutic targets. Coding and non-coding RNAs frequently fold into complex conformations which, if effectively targeted, offer opportunities to therapeutically modulate numerous cellular processes, including those linked to undruggable protein targets. Despite the considerable skepticism as to whether RNAs can be targeted with small molecule therapeutics, overwhelming evidence suggests the challenges we are currently facing are not outside the realm of possibility. In this review, we highlight the most recent advances in molecular techniques that have sparked a revolution in understanding the RNA structure-to-function relationship. We bring attention to the application of these modern techniques to identify druggable RNA targets and to assess small molecule binding specificity. Finally, we discuss novel screening methodologies that support RNA drug discovery and present examples of therapeutically valuable RNA targets. RNA as a drug targetThe vast diversity of RNAs expanding beyond coding transcripts to several classes of ncRNAs that vary in length, biogenesis, polarity, and putative functions, increases the repertoire of druggable targets. 19,20 Here, specific RNA properties contribute to its attractive, yet challenging makeup as a target molecule. RNA can form complex three-dimensional structures through canonical Watson-Crick base pairing and complex tertiary interactions that are mediated by non-canonical bonds. Such structures can be as intricate and stable as those formed by proteins and can recognize small-molecule ligands, other nucleic acids, and/or proteins with high affinity and specificity. [21][22][23][24] At the same time, the highly dynamic conformation and repetitive character of its surface presents difficulties for drug design. 25,26 In addition, many putative small molecule-binding pockets in RNA are much more polar and solvent exposed than binding sites on proteins, complicating ligand design efforts. Compounding these issues, most target RNAs are expressed at low levels, with the exception of ribosomal (rRNA) and transfer (tRNA) RNAs, which constitute 80-90% and 10-15% of total cellular RNA, respectively. 27 Other abundant RNAs, such as messenger (mRNA), small nuclear (snRNA), and small nucleolar (snoRNA) are present at levels that are about 1-2 orders of magnitude lower than rRNA and tRNA. Certain small RNAs, such as micro (miRNA) and piwi (piRNAs) can be present at very high levels; however, this appears to be cell type dependent. One should keep in mind that if the RNA has catalytic activity or if it acts as a scaffold to regulate https://doi.

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“…The Maybridge Ro3 1000 compound diversity library, which includes stock solutions of fragments dissolved in DMSO to a final concentration of 100 m m , was used for the screen. The screen was carried out at 5 m m final fragment concentration, which is typical in fragment screening . The working assay solution, with the ESF probe and the fragments (at 5 m m ), included DMSO at 5.5 % of the final volume.…”

Section: Figurementioning

confidence: 99%

Deploying Fluorescent Nucleoside Analogues for High‐Throughput Inhibitor Screening

2019

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High‐throughput small‐molecule screening in drug discovery processes commonly rely on fluorescence‐based methods including fluorescent polarization and fluorescence/Förster resonance energy transfer. These techniques use highly accessible instrumentation; however, they can suffer from high false‐negative rates and background signals, or might involve complex schemes for the introduction of fluorophore pairs. Herein we present the synthesis and application of fluorescent nucleoside analogues as the foundation for directed approaches for competitive binding analyses. The general approach describes selective fluorescent environment‐sensitive (ES) nucleoside analogues that are adaptable to diverse enzymes that act on nucleoside‐based substrates. We demonstrate screening a set of uridine analogues and development of an assay for fragment‐based lead discovery with the TcdB glycosyltransferase (GT), an enzyme associated with virulence in Clostridium difficile. The uridine‐based probe used for this high‐throughput screen has a KD value of 7.2 μm with the TcdB GT and shows a >30‐fold increase in fluorescence intensity upon binding. The ES‐based probe assay is benchmarked against two other screening approaches.

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Current perspectives in fragment-based lead discovery (FBLD)

Cited by 139 publications

References 58 publications

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Unveiling the druggable RNA targets and small molecule therapeutics

Deploying Fluorescent Nucleoside Analogues for High‐Throughput Inhibitor Screening

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