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Lessons learnt from assembling screening libraries for drug discovery for neglected diseases.

ABSTRACT: To enable the establishment of a drug discovery operation for neglected diseases, out of 2.3 million commercially available compounds 222 552 compounds were selected for an in silico library, 57 438 for a diverse general screening library, and 1 697 compounds for a focused kinase set. Compiling these libraries required a robust strategy for compound selection. Rules for unwanted groups were defined and selection criteria to enrich for lead-like compounds which facilitate straightforward structure-activity relationship exploration were established. Further, a literature and patent review was undertaken to extract key recognition elements of kinase inhibitors ("core fragments") to assemble a focused library for hit discovery for kinases. Computational and experimental characterisation of the general screening library revealed that the selected compounds 1) span a broad range of lead-like space, 2) show a high degree of structural integrity and purity, and 3) demonstrate appropriate solubility for the purposes of biochemical screening. The implications of this study for compound selection, especially in an academic environment with limited resources, are considered.

SUBMITTER: Brenk R

PROVIDER: S-EPMC2628535 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Lessons learnt from assembling screening libraries for drug discovery for neglected diseases.

Brenk Ruth R Schipani Alessandro A James Daniel D Krasowski Agata A Gilbert Ian Hugh IH Frearson Julie J Wyatt Paul Graham PG

ChemMedChem 20080301 3

To enable the establishment of a drug discovery operation for neglected diseases, out of 2.3 million commercially available compounds 222 552 compounds were selected for an in silico library, 57 438 for a diverse general screening library, and 1 697 compounds for a focused kinase set. Compiling these libraries required a robust strategy for compound selection. Rules for unwanted groups were defined and selection criteria to enrich for lead-like compounds which facilitate straightforward structur ...[more]

PMID: 18064617

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Project description:A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

Project description:BackgroundNeglected tropical diseases (NTDs) are closely related to poverty and affect over a billion people in developing countries. The unmet treatment needs cause high mortality and disability thereby imposing a huge burden with severe social and economic consequences. Although coordinated by the World Health Organization, various philanthropic organizations, national governments and the pharmaceutical industry have been making efforts in improving the situation, the control of NTDs is still inadequate and extremely difficult today. The lack of safe, effective and affordable medicines is a key contributing factor. This paper reviews the recent advances and some of the challenges that we are facing in the fight against NTDs.Main bodyIn recent years, a number of innovations have demonstrated propensity to promote drug discovery and development for NTDs. Implementation of multilateral collaborations leads to continued efforts and plays a crucial role in drug discovery. Proactive approaches and advanced technologies are urgently needed in drug innovation for NTDs. However, the control and elimination of NTDs remain a formidable task as it requires persistent international cooperation to make sustainable progresses for a long period of time. Some currently employed strategies were proposed and verified to be successful, which involve both mechanisms of 'Push' which aims at cutting the cost of research and development for industry and 'Pull' which aims at increasing market attractiveness. Coupled to this effort should be the exercise of shared responsibility globally to reduce risks, overcome obstacles and maximize benefits. Since NTDs are closely associated with poverty, it is absolutely essential that the stakeholders take concerted and long-term measures to meet multifaceted challenges by alleviating extreme poverty, strengthening social intervention, adapting climate changes, providing effective monitoring and ensuring timely delivery.ConclusionsThe ongoing endeavor at the global scale will ultimately benefit the patients, the countries they are living and, hopefully, the manufacturers who provide new preventive, diagnostic and therapeutic products.

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Lessons learnt from assembling screening libraries for drug discovery for neglected diseases.

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Lessons learnt from assembling screening libraries for drug discovery for neglected diseases.

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