Computational Approaches and Collaborative Drug Discovery for Trypanosomal Diseases

Ekins, Sean; Bunin, Barry A.

doi:10.1002/9783527670383.ch5

Cited by 4 publications

(3 citation statements)

References 44 publications

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“…Many researchers may wish to prepare D3 structures according to their own protocols. The SMILES string of each D3 compound has also been published on both the D3 (http://durrantlab.com/liglib/iupui/d3_docking/, accessed February 27, 2017) and Collaborative Drug Discovery (CDD) (https://www.collaborativedrug.com, accessed February 27, 2017) websites . CDD also allows researchers to search and download subsets of the entire D3 virtual catalog.…”

Section: Resultsmentioning

confidence: 99%

Documenting and harnessing the biological potential of molecules in Distributed Drug Discovery (D3) virtual catalogs

et al. 2017

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Virtual molecular catalogs have limited utility if member compounds are (i) difficult to synthesize or (ii) unlikely to have biological activity. The Distributed Drug Discovery (D3) program addresses the synthesis challenge by providing scientists with a free virtual D3 catalog of 73,024 easy-to-synthesize N-acyl unnatural α-amino acids, their methyl esters, and primary amides. The remaining challenge is to document and exploit the bioactivity potential of these compounds. In the current work, a search process is described that retrospectively identifies all virtual D3 compounds classified as bioactive hits in PubChem-cataloged experimental assays. The results provide insight into the broad range of drug-target classes amenable to inhibition and/or agonism by D3-accessible molecules. To encourage computer-aided drug discovery centered on these compounds, a publicly available virtual database of D3 molecules prepared for use with popular computer docking programs is also presented.

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Section: Resultsmentioning

confidence: 99%

Documenting and harnessing the biological potential of molecules in Distributed Drug Discovery (D3) virtual catalogs

et al. 2017

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“…In the intervening period we have further developed the CDD Vault software (Box 1) and applied it to many large-scale collaborations for secure sharing of chemistry and biology data. Although we have previously demonstrated the role collaborative software can have in malaria research [22] as part of an integrated drug discovery cycle [23], as well as trypanosomal diseases [24], the focus of this discussion will be on tuberculosis (TB) and it specifically highlights the FP7-funded More Medicines for Tuberculosis (MM4TB) collaboration.…”

Section: Introductionmentioning

confidence: 99%

Collaborative drug discovery for More Medicines for Tuberculosis (MM4TB)

Ekins

Spektor

Clark

et al. 2017

Drug Discovery Today

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Neglected disease drug discovery is generally poorly funded compared with major diseases and hence there is an increasing focus on collaboration and precompetitive efforts such as public–private partnerships (PPPs). The More Medicines for Tuberculosis (MM4TB) project is one such collaboration funded by the EU with the goal of discovering new drugs for tuberculosis. Collaborative Drug Discovery has provided a commercial web-based platform called CDD Vault which is a hosted collaborative solution for securely sharing diverse chemistry and biology data. Using CDD Vault alongside other commercial and free cheminformatics tools has enabled support of this and other large collaborative projects, aiding drug discovery efforts and fostering collaboration. We will describe CDD's efforts in assisting with the MM4TB project.

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“…Trypanosomatid parasites are the causative agents of many neglected tropical diseases, , including the leishmaniases, Chagas disease, and human African trypanosomiasis (sleeping sickness). The prevalence of sleeping sickness has been rapidly decreasing over the past 10 years with the introduction of drugs such as eflornithine, and visceral leishmaniasis is now being treated quite successfully with miltefosine; however, for Chagas disease (caused by Trypanosoma cruzi), there are no truly effective treatments for the chronic stage of the disease, so new drugs, and new drug leads, are of great interest …”

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confidence: 99%

Structures of Trypanosome Vacuolar Soluble Pyrophosphatases: Antiparasitic Drug Targets

Yang

Chen

et al. 2016

ACS Chem. Biol.

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Trypanosomatid parasites are the causative agents of many neglected tropical diseases including the leishmaniases, Chagas disease, and human African trypanosomiasis. They exploit unusual vacuolar soluble pyrophosphatases (VSPs), absent in humans, for cell growth and virulence and as such, are drug targets. Here, we report the crystal structures of VSP1s from Trypanosoma cruzi and T. brucei, together with that of the T. cruzi protein bound to a bisphosphonate inhibitor. Both VSP1s form a hybrid structure containing an (N-terminal) EF-hand domain fused to a (C-terminal) pyrophosphatase domain. The two domains are connected via an extended loop of about 17 residues. Crystallographic analysis and size exclusion chromatography indicate that the VSP1s form tetramers containing head-to-tail dimers. Phosphate and diphosphate ligands bind in the PPase substrate-binding pocket and interact with several conserved residues, and a bisphosphonate inhibitor (BPH-1260) binds to the same site. Based on Cytoscape and other bioinformatics analyses it is apparent that similar folds will be found in most if not all trypanosomatid VSP1s, including those found in insects (Angomonas deanei, Strigomonas culicis), plant pathogens (Phytomonas spp.) and Leishmania spp. Overall, the results are of general interest since they open the way to structure-based drug design for many of the neglected tropical diseases.

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Computational Approaches and Collaborative Drug Discovery for Trypanosomal Diseases

Cited by 4 publications

References 44 publications

Documenting and harnessing the biological potential of molecules in Distributed Drug Discovery (D3) virtual catalogs

Documenting and harnessing the biological potential of molecules in Distributed Drug Discovery (D3) virtual catalogs

Collaborative drug discovery for More Medicines for Tuberculosis (MM4TB)

Structures of Trypanosome Vacuolar Soluble Pyrophosphatases: Antiparasitic Drug Targets

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