Target-based drug discovery: is something wrong?

Sams-Dodd, Frank

doi:10.1016/s1359-6446(04)03316-1

Cited by 479 publications

(337 citation statements)

References 27 publications

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“…Extensive research over the last half century has made clear that most chronic illnesses can only be cured by multitargeted, as opposed to mono-targeted, therapy [204][205][206] and that promiscuous targeting of a disease cell's multiple bypass mechanisms is a therapeutic virtue [207]. Consequently, agents that can modulate multiple cellular targets are now attractive objects of research.…”

Section: Discussionmentioning

confidence: 99%

Curcumin as “Curecumin”: From kitchen to clinic

Goel

Kunnumakkara

Aggarwal

2008

Biochemical Pharmacology

1,945

1,290

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Section: Discussionmentioning

confidence: 99%

Curcumin as “Curecumin”: From kitchen to clinic

Goel

Kunnumakkara

Aggarwal

2008

Biochemical Pharmacology

1,945

1,290

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“…Metabolomics illustrates this amply. There is also the view that the perceived decrease in the effectiveness of the target-based drug discovery process [3][4][5], including the still-high levels of attrition [6], means that we must move towards understanding organisms at something more akin to a whole-system level [7][8][9][10][11].…”

Section: Systems Biology and Metabolic Modelling In The 21st Centurymentioning

confidence: 99%

Systems biology, metabolic modelling and metabolomics in drug discovery and development

Kell

2006

Drug Discovery Today

266

163

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Unlike signalling pathways, metabolic networks are subject to strict stoichiometric constraints. Metabolomics amplifies changes in the proteome, and represents more closely the phenotype of an organism. Recent advances enable the production (and computer-readable encoding as SBML) of metabolic network models reconstructed from genome sequences, as well as experimental measurements of much of the metabolome. There is increasing convergence between the number of human metabolites estimated via genomics ( 3000) and the number measured experimentally. It is thus both timely, and now possible, to bring these two approaches together as an integrated (if distributed) whole to help understand the genesis of metabolic biomarkers, the progress of disease, and the modes of action, efficacy, off-target effects and toxicity of pharmaceutical drugs. Systems biology and metabolic modelling in the 21st CenturyAlthough there are many individual definitions, most commentators (including this one [1,2]) take it that systems biology involves an iterative interplay between more or less high-throughput and high-content 'wet' experiments, technology development, theory and computational modelling, and that it is the involvement of computational modelling, in particular, in the process that sets systems biology apart from the more traditional and more reductionist molecular biology. Metabolomics illustrates this amply. There is also the view that the perceived decrease in the effectiveness of the target-based drug discovery process [3][4][5], including the still-high levels of attrition [6], means that we must move towards understanding organisms at something more akin to a whole-system level [7][8][9][10][11].The question then arises as to what part of a system one might first beneficially model? Although there has, unsurprisingly, been considerable interest in modelling the major signalling pathways (e.g. Refs [12,13]), there are several reasons why it is timely to turn our attention to the level of small molecule metabolism, which is the focus of this review. Metabolism is more discriminatingIt has long been known, and proven through the formalism of metabolic control analysis [7,10,[14][15][16], that whereas small changes in the concentrations of enzymes (and the transcripts that encode them) have only small effects on the fluxes through metabolic pathways, they have substantial effects on the concentrations of metabolic intermediates. Because the metabolome (nominally the concentrations of 'all' the metabolites measured in a system of interest [17]) is downstream of the proteome, it is thereby 'amplified' both in theory [18] and in practice [19,20] and represents a more sensitive level of organisation than do the macromolecular 'omes for understanding a complex biological system, and the changes in it that might be occasioned by disease or pharmaceutical intervention [21,22]. Metabolic reconstruction is now mature and timelyAn attractive feature for the purposes of modelling is that metabolism, in contrast to signalling pathways, ...

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“…It has been suggested that 'selectively nonselective' drugs, or 'magic shotguns,' can already be developed and may fill a clinical need for improved therapeutics. 31,44 Indeed, genomics-based screening approaches are being used to identify novel drug candidates based on their ability to either mimic the gene expression 'signature' of gold-standard drugs like clozapine, or based on their ability to normalize the expression of genes that are altered in schizophrenia. 45 Alternatively, high-throughput behavioral screenings may prove useful for the identification of novel medications for schizophrenia, 45 though hurdles exist in finding animal behavioral models with good predictive value.…”

Section: Moving Towards the Futurementioning

confidence: 99%

“…In recent years, a number of authors have proposed that designing selectively non-selective drugs that interact with several molecular targets (coined 'magic shotguns') 31 will lead to more effective medications for a variety of complex disorders. 31,44,45 We will briefly review the individual molecular targets that may have a role in these 'magic shotguns' or in a polypharmacy approach targeting the various clinical symptom domains of schizophrenia (Table 3). Where available, references to key review articles are provided.…”

Section: Introductionmentioning

confidence: 99%

The pipeline and future of drug development in schizophrenia

2007

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While the current antipsychotic medications have profoundly impacted the treatment of schizophrenia over the past 50 years, the newer atypical antipsychotics have not fulfilled initial expectations, and enormous challenges remain in long-term treatment of this debilitating disease. In particular, improved treatment of the negative symptoms and cognitive dysfunction in schizophrenia which greatly impact overall morbidity is needed. In this review we will briefly discuss the current pipeline of drugs for schizophrenia, outlining many of the strategies and targets currently under investigation for the development of new schizophrenia drugs. Many of these compounds have great potential as augmenting agents in the treatment of negative symptoms and cognition. In addition, we will highlight the importance of developing new paradigms for drug discovery in schizophrenia and call for an increased role of academic scientists in discovering and validating novel drug targets. Indeed, recent breakthroughs in genetic studies of schizophrenia are allowing for the development of hypothesis-driven approaches for discovering possible disease-modifying drugs for schizophrenia. Thus, this is an exciting and pivotal time for the development of truly novel approaches to drug development and treatment of complex disorders like schizophrenia.

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Target-based drug discovery: is something wrong?

Cited by 479 publications

References 27 publications

Curcumin as “Curecumin”: From kitchen to clinic

Curcumin as “Curecumin”: From kitchen to clinic

Systems biology, metabolic modelling and metabolomics in drug discovery and development

The pipeline and future of drug development in schizophrenia

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