Application of Computer-Aided Drug Repurposing in the Search of New Cruzipain Inhibitors: Discovery of Amiodarone and Bromocriptine Inhibitory Effects

Bellera, Carolina L.; Balcazar, Darío Emmanuel; Alberca, Lucas Nicolás; Labriola, Carlos; Talevi, Alan; Carrillo, Carolina

doi:10.1021/ci400284v

Cited by 36 publications

(26 citation statements)

References 39 publications

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“…Other compounds have been identified by drug repositioning as possible trypanocidal drugs using different targets; such as the cruzipain (56–59), some T. cruzi kinases (60–62) and the trans-sialidase (63), among other examples. Other drug repurposing approaches have inferred the possible trypanocidal activity of already-approved drugs based on the reported effect or mechanism of action of some compounds in other organisms (64–69).…”

Section: Discussionmentioning

confidence: 99%

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Sayé

Gauna

Valera-Vera

et al. 2019

Preprint

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BackgroundCrystal violet (CV) was used for several years in blood banks to eliminate the parasite Trypanosoma cruzi in endemic areas in order to prevent transfusion-transmitted Chagas disease. One mechanism of action described for CV involves inhibition of proline uptake. In T. cruzi, proline is essential for host cell infection and intracellular differentiation among other processes, and can be obtained through the proline permease TcAAAP069.Methodology/Principal FindingsCV inhibited proline transporter TcAAAP069 and parasites overexpressing this permease were 47-fold more sensitive to this compound than control parasites. Using CV as reference molecule, loratadine, cyproheptadine, olanzapine and clofazimine were identified as structurally related compounds to CV (structural analogues) by in silico drug repurposing through a similarity-based virtual screening protocol. All these already-approved drugs for clinical use inhibited TcAAAP069 activity with different efficacies and also presented trypanocidal action in epimastigotes, trypomastigotes and amastigotes of the Y strain. Additionally, loratadine, cyproheptadine and clofazimine showed trypanocidal effect on epimastigotes of the CL Brener and DM28c strains. Finally, a synergistic effect between benznidazole and the CV chemical analogues was evidenced by combination and dose-reduction indexes values in epimastigotes of the Y strain.Conclusions/SignificanceLoratadine, cyproheptadine and clofazimine inhibit TcAAAP069 proline transporter and also present trypanocidal effect against all T. cruzi life stages. These CV structural analogues could be a starting point to design therapeutic alternatives to treat Chagas disease by finding new indications for old drugs. This approach, called drug repurposing is a recommended strategy by the World Health Organization to treat neglected diseases, like Chagas disease, and combination therapy may improve the possibility of success of repositioned drugs.Author summaryChagas disease, caused by the parasite Trypanosoma cruzi, affects 7 million people worldwide. Despite there are two drugs available since 50 years ago, the therapy present severe side effects and is not effective in the chronic phase of the disease were most of the patients are diagnosed. Crystal violet (CV) was utilized as additive in blood banks to prevent transfusion-transmitted Chagas disease. Proline is involved in many pathways, like infection establishment and life cycle progression. In this work we first demonstrate that CV has the proline permease TcAAAP069 as one of its molecular targets. Then we search in a database of already-approved drugs for compounds that were structurally related to CV under the premise “similar structure, similar activity”. We identified three drugs that inhibit proline transport and present at least the same trypanocidal effect than benznidazole, the current treatment for Chagas disease. Finally we observed a synergistic effect with the multidrug combination therapy. Drug discovery is an expensive and time-consuming process and Chagas disease is associated with poverty. The discovery of new indications to old drugs, called drug repurposing, can facilitate a rapid and more profitable therapy application since preclinical trials and pharmacokinetic studies are already available.

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Section: Discussionmentioning

confidence: 99%

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Sayé

Gauna

Valera-Vera

et al. 2019

Preprint

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“…Although dopamine signaling and metabolism are tightly linked, the exact mechanism of action of bromocriptine in diabetes is partially unknown [27]. More recently, an anti- Trypanosoma cruzi effect has been studied for bromocriptine [28], unlikely through dopamine receptor signaling. Taking into account that cancer stem cells (including LSCs) depend on dopamine signaling and its inhibition compromises their viability [29], the anti-AML cytotoxic effect shown here might be exerted by D4 dopamine receptor antagonism and/or other alternative mechanism.…”

Section: Discussionmentioning

confidence: 99%

Repositioning of bromocriptine for treatment of acute myeloid leukemia

et al. 2016

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BackgroundTreatment for acute myeloid leukemia (AML) has not significantly changed in the last decades and new therapeutic approaches are needed to achieve prolonged survival rates. Leukemia stem cells (LSC) are responsible for the initiation and maintenance of AML due to their stem-cell properties. Differentiation therapies aim to abrogate the self-renewal capacity and diminish blast lifespan.MethodsAn in silico screening was designed to search for FDA-approved small molecules that potentially induce differentiation of AML cells. Bromocriptine was identified and validated in an in vitro screening. Bromocriptine is an approved drug originally indicated for Parkinson’s disease, acromegaly, hyperprolactinemia and galactorrhoea, and recently repositioned for diabetes mellitus.ResultsTreatment with bromocriptine reduced cell viability of AML cells by activation of the apoptosis program and induction of myeloid differentiation. Moreover, the LSC-enriched primitive AML cell fraction was more sensitive to the presence of bromocriptine. In fact, bromocriptine decreased the clonogenic capacity of AML cells. Interestingly, a negligible effect is observed in healthy blood cells and hematopoietic stem/progenitor cells.ConclusionsOur results support the use of bromocriptine as an anti-AML drug in a repositioning setting and the further clinical validation of this preclinical study.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1007-5) contains supplementary material, which is available to authorized users.

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“…Commonly known as “drug repositioning” [9-12], finding new uses of existing drugs with known toxicity and safety profiles, enables pharmaceutical companies and researchers to accelerate drug development by 15-20%, resulting in a reduction of time and cost by a minimum of 2-3 years in drug development program duration [12]. There have been several examples of drugs that have been successfully repositioned, such as Amphotericin B [13], Aspirin ® [14], and Bromocriptine [15]. Such drug repositioning strategies [16] not only promise reduction in cost and time but also result in higher chances of success at the clinical level [9].…”

Section: Introductionmentioning

confidence: 99%

Multiscale Modelling of Relationships between Protein Classes and Drug Behavior Across all Diseases Using the CANDO Platform

Sethi¹,

Chopra²,

Samudrala³

2015

MRMC

147

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We have examined the effect of eight different protein classes (channels, GPCRs, kinases, ligases, nuclear receptors, proteases, phosphatases, transporters) on the benchmarking performance of the CANDO drug discovery and repurposing platform (http://protinfo.org/cando). The first version of the CANDO platform utilizes a matrix of predicted interactions between 48278 proteins and 3733 human ingestible compounds (including FDA approved drugs and supplements) that map to 2030 indications/diseases using a hierarchical chem and bio-informatic fragment based docking with dynamics protocol (> one billion predicted interactions considered). The platform uses similarity of compound-proteome interaction signatures as indicative of similar functional behavior and benchmarking accuracy is calculated across 1439 indications/diseases with more than one approved drug. The CANDO platform yields a significant correlation (0.99, p-value < 0.0001) between the number of proteins considered and benchmarking accuracy obtained indicating the importance of multitargeting for drug discovery. Average benchmarking accuracies range from 6.2 % to 7.6 % for the eight classes when the top 10 ranked compounds are considered, in contrast to a range of 5.5 % to 11.7 % obtained for the comparison/control sets consisting of 10, 100, 1000, and 10000 single best performing proteins. These results are generally two orders of magnitude better than the average accuracy of 0.2% obtained when randomly generated (fully scrambled) matrices are used. Different indications perform well when different classes are used but the best accuracies (up to 11.7% for the top 10 ranked compounds) are achieved when a combination of classes are used containing the broadest distribution of protein folds. Our results illustrate the utility of the CANDO approach and the consideration of different protein classes for devising indication specific protocols for drug repurposing as well as drug discovery.

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Application of Computer-Aided Drug Repurposing in the Search of New Cruzipain Inhibitors: Discovery of Amiodarone and Bromocriptine Inhibitory Effects

Cited by 36 publications

References 39 publications

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Crystal violet structural analogues identified by in silico drug repositioning present anti-Trypanosoma cruzi activity through inhibition of proline transporter TcAAAP069

Repositioning of bromocriptine for treatment of acute myeloid leukemia

Multiscale Modelling of Relationships between Protein Classes and Drug Behavior Across all Diseases Using the CANDO Platform

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