Chemical probes for biological systems

Garcia-Serna, Ricard; Mestres, Jordi

doi:10.1016/j.drudis.2010.11.004

Cited by 24 publications

(28 citation statements)

References 24 publications

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“…An unexpected lesson of this work is that most drugs do in fact have reasonable primary molecular targets, and so we wondered if this point could be taken a step further: For how many drugs is potency and specificity well-enough known to identify them as chemical probes of biology? The distinction between drugs, which must be therapeutically efficacious but can often be promiscuous, and probes, which must have a high-fidelity to their targets but can be therapeutically ineffective, has been well established (34,35). We wondered, nevertheless, whether some drugs might have the specificity requirements to meet the common criteria of probes (36).…”

Section: Drugs Asmentioning

confidence: 99%

Identifying mechanism-of-action targets for drugs and probes

Gregori‐Puigjané

Setola

Hert

et al. 2012

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

165

141

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Notwithstanding their key roles in therapy and as biological probes, 7% of approved drugs are purported to have no known primary target, and up to 18% lack a well-defined mechanism of action. Using a chemoinformatics approach, we sought to "de-orphanize" drugs that lack primary targets. Surprisingly, targets could be easily predicted for many: Whereas these targets were not known to us nor to the common databases, most could be confirmed by literature search, leaving only 13 Food and Drug Administration-approved drugs with unknown targets; the number of drugs without molecular targets likely is far fewer than reported. The number of worldwide drugs without reasonable molecular targets similarly dropped, from 352 (25%) to 44 (4%). Nevertheless, there remained at least seven drugs for which reasonable mechanism-of-action targets were unknown but could be predicted, including the antitussives clemastine, cloperastine, and nepinalone; the antiemetic benzquinamide; the muscle relaxant cyclobenzaprine; the analgesic nefopam; and the immunomodulator lobenzarit. For each, predicted targets were confirmed experimentally, with affinities within their physiological concentration ranges. Turning this question on its head, we next asked which drugs were specific enough to act as chemical probes. Over 100 drugs met the standard criteria for probes, and 40 did so by more stringent criteria. A chemical information approach to drug-target association can guide therapeutic development and reveal applications to probe biology, a focus of much current interest. chemical tools | drug target identification | polypharmacology

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Section: Drugs Asmentioning

confidence: 99%

Identifying mechanism-of-action targets for drugs and probes

Gregori‐Puigjané

Setola

Hert

et al. 2012

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

165

141

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“…For example, Modafinil is a drug marketed for wakefulness disorders discovered in the 1970s for which the molecular mechanism of action remains unknown. As well, antipsychotics often show a complex polypharmacology that is required for efficacy but their mechanism is not well understood (Roth et al, 2004; Garcia-Serna and Mestres, 2011), this is discussed further below. Therefore, while it may be useful to study the underlying mechanisms of drugs using chemical biology techniques, efforts employing certain drugs to help understand the mechanisms underlying biological activity could be challenging requiring the combination of chemical and systems biology approaches to fully leverage such compounds.…”

Section: Categories Of Compounds Employed In Focus Librariesmentioning

confidence: 99%

Composition and applications of focus libraries to phenotypic assays

Wassermann¹,

Camargo²,

Auld³

2014

Front. Pharmacol.

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The wealth of bioactivity information now available on low-molecular weight compounds has enabled a paradigm shift in chemical biology and early phase drug discovery efforts. Traditionally chemical libraries have been most commonly employed in screening approaches where a bioassay is used to characterize a chemical library in a random search for active samples. However, robust curating of bioassay data, establishment of ontologies enabling mining of large chemical biology datasets, and a wealth of public chemical biology information has made possible the establishment of highly annotated compound collections. Such annotated chemical libraries can now be used to build a pathway/target hypothesis and have led to a new view where chemical libraries are used to characterize a bioassay. In this article we discuss the types of compounds in these annotated libraries composed of tools, probes, and drugs. As well, we provide rationale and a few examples for how such libraries can enable phenotypic/forward chemical genomic approaches. As with any approach, there are several pitfalls that need to be considered and we also outline some strategies to avoid these.

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“…Using phenotypic methods to identify hits, empirical medicinal chemistry to optimize them, and in vivo pharmacokinetic, toxicokinetic, and pharmacodynamic models to understand their function, a drug discovery program can remove target identification from the critical path needed to move new drugs to the clinic (Figure 3). However, having a target for a small molecule series is practical and useful because it allows the use of both structural and biochemical methods (Stoll, et al, 2011; Wilson and Lill, 2011) and can direct the focus of toxicologic studies (Garcia-Serna and Mestres, 2010; Garcia-Serna and Mestres, 2011). Additionally, in malaria drug development, knowing a target for the drug facilitates the study of the acquisition of resistance.…”

Section: Target Identificationmentioning

confidence: 99%

Global Phenotypic Screening for Antimalarials

Guiguemde

Shelat

Garcia-Bustos

et al. 2012

Chemistry & Biology

133

119

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Malaria, a devastating infectious disease caused by Plasmodium spp., leads to roughly 655,000 deaths per year, mostly of African children. To compound the problem, drug resistance has emerged to all classical antimalarials and may be emerging for artemisinin-based combination therapies. To address the need for new antimalarials with novel mechanisms, several groups carried out phenotypic screening campaigns to identify compounds inhibiting growth of the blood stages of Plasmodium falciparum. In this review, we describe the characterization of these compounds, explore currently ongoing strategies to develop lead molecules, and endorse the concept of a “malaria box” of publicly accessible active compounds.

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Chemical probes for biological systems

Cited by 24 publications

References 24 publications

Identifying mechanism-of-action targets for drugs and probes

Identifying mechanism-of-action targets for drugs and probes

Composition and applications of focus libraries to phenotypic assays

Global Phenotypic Screening for Antimalarials

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