Prediction of the P. falciparum Target Space Relevant to Malaria Drug Discovery

Spitzmüller, Andreas; Mestres, Jordi

doi:10.1371/journal.pcbi.1003257

Cited by 38 publications

(28 citation statements)

References 64 publications

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“…31 predicted the target space for the St Jude's and TCAMS whole-cell hit compounds and found over 200 P. falciparum hit proteins for 20,000 compounds. However, until recently, data for βH inhibitors has been largely unavailable.…”

Section: Resultsmentioning

confidence: 99%

Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity

Wicht¹,

Combrinck²,

Smith³

et al. 2015

Bioorganic & Medicinal Chemistry

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A large quantity of high throughput screening (HTS) data for antimalarial activity has become available in recent years. This includes both phenotypic and target-based activity. Realising the maximum value of these data remains a challenge. In this respect, methods that allow such data to be used for virtual screening maximise efficiency and reduce costs. In this study both in vitro antimalarial activity and inhibitory data for β-haematin formation, largely obtained from publically available sources, has been used to develop Bayesian models for inhibitors of β-haematin formation and in vitro antimalarial activity. These models were used to screen two in silico compound libraries. In the first, the 1510 U.S. Food and Drug Administration approved drugs available on PubChem were ranked from highest to lowest Bayesian score based on a training set of β-haematin inhibiting compounds active against P. falciparum that did not include any of the clinical antimalarials or close analogues. The six known clinical antimalarials that inhibit β-haematin formation were ranked in the top 2.1% of compounds. Furthermore, the in vitro antimalarial hit-rate for this prioritised set of compounds was found to be 81% in the case of the subset where activity data are available in PubChem. In the second, a library of about 5,000 commercially available compounds (AldrichCPR) was virtually screened for ability to inhibit β-haematin formation and then for in vitro antimalarial activity. A selection of 34 compounds was purchased and tested, of which 24 were predicted to be β-haematin inhibitors. The hit rate for inhibition of β-haematin formation was found to be 25% and a third of these were active against P. falciparum, corresponding to enrichments estimated at about 25- and 140-fold relative to random screening, respectively.

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Section: Resultsmentioning

confidence: 99%

Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity

Wicht¹,

Combrinck²,

Smith³

et al. 2015

Bioorganic & Medicinal Chemistry

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“…PHRAG and FPD were used to calculate the similarity between two molecules that account for the overlapping fraction of their active profiles, and SHED was responsible for computing the Euclidean distance [50]. PredictFX 1.1 has been successfully adopted by others [51,52,53] in identification of novel targets of small molecules.…”

Section: Methodsmentioning

confidence: 99%

Discovery of a New Class of Cathepsin K Inhibitors in Rhizoma Drynariae as Potential Candidates for the Treatment of Osteoporosis

Qiu

Dong

Dai

et al. 2016

IJMS

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Rhizoma Drynariae (RD), as one of the most common clinically used folk medicines, has been reported to exert potent anti-osteoporotic activity. The bioactive ingredients and mechanisms that account for its bone protective effects are under active investigation. Here we adopt a novel in silico target fishing method to reveal the target profile of RD. Cathepsin K (Ctsk) is one of the cysteine proteases that is over-expressed in osteoclasts and accounts for the increase in bone resorption in metabolic bone disorders such as postmenopausal osteoporosis. It has been the focus of target based drug discovery in recent years. We have identified two components in RD, Kushennol F and Sophoraflavanone G, that can potentially interact with Ctsk. Biological studies were performed to verify the effects of these compounds on Ctsk and its related bone resorption process, which include the use of in vitro fluorescence-based Ctsk enzyme assay, bone resorption pit formation assay, as well as Receptor Activator of Nuclear factor κB (NF-κB) ligand (RANKL)-induced osteoclastogenesis using murine RAW264.7 cells. Finally, the binding mode and stability of these two compounds that interact with Ctsk were determined by molecular docking and dynamics methods. The results showed that the in silico target fishing method could successfully identify two components from RD that show inhibitory effects on the bone resorption process related to protease Ctsk.

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“…tubulins) and protein families involved in epigenetic mechanisms have been identified as having multitarget potential [57]. Members of these protein families are currently considered as recently validated or revived antimalarial targets within the MMV pipeline including falcipain-cystein proteases 2-3 and aspartic protease plasmepsins I, II, IV [10].…”

Section: Inhibiting Multiple Related Targetsmentioning

confidence: 99%

“…antimalarials that target 39 high-ranking proteins; 85% of this target space falls within multitarget profiles [57]. These compounds could serve as a multitarget pool displaying polypharmacology and is worth investigation for their potential as resistance-resistant antimalarial candidates.…”

Section: Defining a Target And Chemical Space Relevant To Resisting /mentioning

confidence: 99%

Resisting resistance: is there a solution for malaria?

Verlinden

Louw

Birkholtz

2016

Expert Opinion on Drug Discovery

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IntroductionCurrently, widely used antimalarial drugs have a limited clinical lifespan due to parasite resistance development. With resistance continuously rising, antimalarial drug discovery requires strategies to decrease the time of delivering a new antimalarial drug while simultaneously increasing the drug"s therapeutic lifespan. Areas coveredLessons learnt from various chemotherapeutic resistance studies in the fields of antibiotic and cancer research offer potentially useful strategies that can be applied to antimalarial drug discovery. In this review we discuss current strategies to circumvent resistance in malaria and alternatives that could be employed. Expert opinionWe have been "beating back" the malaria parasite with novel drugs for the past 49 years but the constant rise in antimalarial drug resistance is forcing the drug discovery community to explore alternative strategies. Avant-garde anti-resistance strategies from alternative fields may assist our endeavors to manage, control and prevent antimalarial drug resistance to progress beyond beating the resistant parasite back, to stopping it dead in its tracks. Here we investigate the 2 development of strategies that are able to either overwhelm or outwit the parasite in its attempts to develop resistance. Article Highlights box In most instances the malaria parasite develops drug resistance at a faster rate than a novel antimalarial drug can be developed. For antimalarial drug discovery to remain sustainable, the clinical lifespan of an antimalarial drug must as least exceed the time taken to develop the drug. Currently, antimalarial drug resistance is being controlled through the development of novel drugs, which are combined with an appropriate drug partner into a combination therapy. Polypharmacology (multitargeting) may be able to speed up the delivery of a novel antimalarial drug while simultaneously increasing the clinical lifespan of the drug. Unexplored targets such as the virulence potential, hijacked host factors and stress factors may deliver drugs that can effectively resist resistance. Other post-resistance strategies such as molecular decoys and chemogenomics may also prove valuable in curbing resistance.

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Prediction of the P. falciparum Target Space Relevant to Malaria Drug Discovery

Cited by 38 publications

References 64 publications

Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity

Bayesian models trained with HTS data for predicting β-haematin inhibition and in vitro antimalarial activity

Discovery of a New Class of Cathepsin K Inhibitors in Rhizoma Drynariae as Potential Candidates for the Treatment of Osteoporosis

Resisting resistance: is there a solution for malaria?

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