Increasing the delivery of next generation therapeutics from high throughput screening libraries

Wigglesworth, Mark; Murray, David C.; Blackett, Carolyn; Kossenjans, Michael; Nissink, J. Willem M.

doi:10.1016/j.cbpa.2015.04.006

Cited by 33 publications

(24 citation statements)

References 42 publications

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“…Given that large-scale screening continues to be a practical and productive entry to successful drug discovery [40,41], the availability of a novel, high-quality screening collection cannot be emphasized enough [42]. During the past year and a half of work, the ELF Chemistry Consortium has implemented an innovative compound library factory based on a collaborative approach between chemistry-focused academic groups and SMEs.…”

Section: Discussionmentioning

confidence: 99%

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Karawajczyk¹,

Giordanetto²,

Benningshof³

et al. 2015

Drug Discovery Today

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High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes.

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Section: Discussionmentioning

confidence: 99%

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Karawajczyk¹,

Giordanetto²,

Benningshof³

et al. 2015

Drug Discovery Today

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show abstract

“…This is particularly true for focused libraries, which may inadvertently become enriched with non-stoichiometric inhibitors if these are not filtered out by appropriate selection criteria. [2] Over the same time, it has become apparent that non-stoichiometric inhibitors come in a variety of flavors, and their different mechanisms are much better understood now. As discussed above, methods and assays to detect at least the major categories of nonstoichiometric inhibitors do exist, even if it may not be straightforward to unambiguously distinguish them in practice.…”

Section: Managing Non-stoichiometric Inhibition By Integrated Lead Fimentioning

confidence: 99%

“…As high-throughput screening (HTS) [1] continues to mature, [2] the need to critically examine raw, primary screening hit lists in order to eliminate non-stoichiometric inhibitors before initiating major downstream efforts is now generally accepted, not just in the pharmaceutical industry but also in academic drug discovery labs. [3][4][5] In this context, the diverse effects that low-molecular weight (LMW) compounds can exhibit in screening assays as well as the underlying mechanisms have been examined in more and more detail.…”

Section: Introductionmentioning

confidence: 99%

Non-stoichiometric inhibition in integrated lead finding – a literature review

Klumpp

2015

Expert Opinion on Drug Discovery

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Over the last few years, awareness of non-stoichiometric inhibitors within screening libraries and HTS hit lists has considerably increased, not only in the pharmaceutical industry but also in the academic drug discovery community. This has resulted in a variety of methods to detect and handle such compounds. These range from in silico approaches to flag suspicious compounds, and counterassays to measure non-stoichiometric inhibition, to biophysical methods that positively demonstrate stoichiometric binding. In addition, novel technologies to verify target engagement within cells are becoming available. While still a time- and resource-consuming nuisance, non-stoichiometric inhibitors therefore do not fundamentally jeopardize the discovery of low molecular weight lead and drug candidates. Rather, they should be viewed as a manageable issue that with appropriate expertise can be overcome through integration of the above-mentioned approaches.

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“…Many methods of drug development have passed through fashion, from high-throughput screening [1], to targeted molecular design [2] and natural product selection [3]. A technique that has been re-invented at regular intervals (usually with a new name) is one that ironically also re-invents the drugs in question.…”

Section: Introductionmentioning

confidence: 99%

Pimping up Drugs Recovered, Superannuated and Under Exploited Drugs - An Introduction to the Basics of Drug Reprofiling

Dilly¹,

Morris

2017

CDDT

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Drug development has moved along way forward from the days of with doctors peddling cauldrons of herbs and spices, however, the process can still miss opportunities for full exploitation of a drug’s potential. Drug reprofiling provides a chance for an established or a forgotten drug to move into a new area of therapy, whether related to the known effects or in a completely new area. In an era of environmental awareness and spiraling costs for traditional drug development, a strategy to squeeze every benefit out of drugs with known safety, tolerability and pharmacological parameters must be a strategically sound desire. We explore examples of success in reprofiling, draw comparisons between techniques, and finally provide two examples from the Valirx plc development pipeline currently undergoing the process.

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Increasing the delivery of next generation therapeutics from high throughput screening libraries

Cited by 33 publications

References 42 publications

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Non-stoichiometric inhibition in integrated lead finding – a literature review

Pimping up Drugs Recovered, Superannuated and Under Exploited Drugs - An Introduction to the Basics of Drug Reprofiling

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