Essential Metabolites of Mycobacterium tuberculosis and Their Mimics

Lamichhane, Gyanu; Freundlich, Joel S.; Ekins, Sean; Wickramaratne, Niluka; Nolan, Scott T.; Bishai, William R.

doi:10.1128/mbio.00301-10

Cited by 59 publications

(61 citation statements)

References 44 publications

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“…The MicroSource set had previously been screened with the published Ebola common feature pharmacophore 26, 27 , using the van der Waals surface of amodiaquine (which was more potent than chloroquine 3 ) to limit the number of hits retrieved 42– 44 . Two of the three selected – compounds quinacrine (fit score 2.59) and tilorone (fit score 3.65) – were retrieved previously.…”

Section: Resultsmentioning

confidence: 99%

Machine learning models identify molecules active against the Ebola virus in vitro

et al. 2016

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The search for small molecule inhibitors of Ebola virus (EBOV) has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs) with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC 50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in vitro.

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Section: Resultsmentioning

confidence: 99%

Machine learning models identify molecules active against the Ebola virus in vitro

et al. 2016

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“…The contributions of this study are 1) further validation of Bayesian models of Mtb whole cell efficacy to deliver actives with a high degree of enrichment over random sampling and 2) demonstration of the utility of SMARTS filters to suggest potential liabilities and for refinement of either the chemical library input or hit set output for a screen. These along with similar cheminformatics methods (18,19) could help to identify new molecules that could become useful probes of Mtb essential biology or inspire novel antitubercular leads or drugs.…”

Section: Introductionmentioning

confidence: 99%

Validating New Tuberculosis Computational Models with Public Whole Cell Screening Aerobic Activity Datasets

Ekins

Freundlich

2011

Pharm Res

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“…Hence, urgent efforts to develop new antitubercular drugs are underway, and, as a consequence, several other compounds for TB treatment are undergoing clinical trials (12,13). The prolonged time of treatment and the upsurge of strains resistant to the currently used drugs underscore the requirement for development of novel molecules which can inhibit the function of essential proteins (14) by interfering with their reaction, leading to the cytotoxicity.…”

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Targeting Mycobacterium tuberculosis Topoisomerase I by Small-Molecule Inhibitors

Godbole

Ahmed

Bhat

et al. 2015

Antimicrob Agents Chemother

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We describe inhibition of Mycobacterium tuberculosis topoisomerase I (MttopoI), an essential mycobacterial enzyme, by two related compounds, imipramine and norclomipramine, of which imipramine is clinically used as an antidepressant. These molecules showed growth inhibition of both Mycobacterium smegmatis and M. tuberculosis cells. The mechanism of action of these two molecules was investigated by analyzing the individual steps of the topoisomerase I (topoI) reaction cycle. The compounds stimulated cleavage, thereby perturbing the cleavage-religation equilibrium. Consequently, these molecules inhibited the growth of the cells overexpressing topoI at a low MIC. Docking of the molecules on the MttopoI model suggested that they bind near the metal binding site of the enzyme. The DNA relaxation activity of the metal binding mutants harboring mutations in the DxDxE motif was differentially affected by the molecules, suggesting that the metal coordinating residues contribute to the interaction of the enzyme with the drug. Taken together, the results highlight the potential of these small molecules, which poison the M. tuberculosis and M. smegmatis topoisomerase I, as leads for the development of improved molecules to combat mycobacterial infections. Moreover, targeting metal coordination in topoisomerases might be a general strategy to develop new lead molecules.

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Essential Metabolites of Mycobacterium tuberculosis and Their Mimics

Cited by 59 publications

References 44 publications

Machine learning models identify molecules active against the Ebola virus in vitro

Machine learning models identify molecules active against the Ebola virus in vitro

Validating New Tuberculosis Computational Models with Public Whole Cell Screening Aerobic Activity Datasets

Targeting Mycobacterium tuberculosis Topoisomerase I by Small-Molecule Inhibitors

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