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Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen

Sharlow, ER and Close, D and Shun, T and Leimgruber, S and Reed, R and Mustata, G and Wipf, P and Johnson, J and O'Neil, M and Grögl, M and Magill, AJ and Lazo, JS (2009) Identification of potent chemotypes targeting Leishmania major using a high-throughput, low-stringency, computationally enhanced, small molecule screen. PLoS Neglected Tropical Diseases, 3 (11).

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Abstract

Patients with clinical manifestations of leishmaniasis, including cutaneous leishmaniasis, have limited treatment options, and existing therapies frequently have significant untoward liabilities. Rapid expansion in the diversity of available cutaneous leishmanicidal chemotypes is the initial step in finding alternative efficacious treatments. To this end, we combined a low-stringency Leishmania major promastigote growth inhibition assay with a structural computational filtering algorithm. After a rigorous assay validation process, we interrogated ∼200,000 unique compounds for L. major promastigote growth inhibition. Using iterative computational filtering of the compounds exhibiting >50% inhibition, we identified 553 structural clusters and 640 compound singletons. Secondary confirmation assays yielded 93 compounds with EC50s ≤ 1 μM, with none of the identified chemotypes being structurally similar to known leishmanicidals and most having favorable in silico predicted bioavailability characteristics. The leishmanicidal activity of a representative subset of 15 chemotypes was confirmed in two independent assay formats, and L. major parasite specificity was demonstrated by assaying against a panel of human cell lines. Thirteen chemotypes inhibited the growth of a L. major axenic amastigote-like population. Murine in vivo efficacy studies using one of the new chemotypes document inhibition of footpad lesion development. These results authenticate that low stringency, large-scale compound screening combined with computational structure filtering can rapidly expand the chemotypes targeting in vitro and in vivo Leishmania growth and viability.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Sharlow, ER
Close, Ddac71@pitt.eduDAC71
Shun, T
Leimgruber, S
Reed, R
Mustata, G
Wipf, Ppwipf@pitt.eduPWIPF
Johnson, J
O'Neil, M
Grögl, M
Magill, AJ
Lazo, JSlazo@pitt.eduLAZO
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorGhedin, Elodieelg21@pitt.eduELG21UNSPECIFIED
Date: 1 November 2009
Date Type: Publication
Journal or Publication Title: PLoS Neglected Tropical Diseases
Volume: 3
Number: 11
DOI or Unique Handle: 10.1371/journal.pntd.0000540
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
School of Medicine > Computational Biology
Refereed: Yes
MeSH Headings: Antiprotozoal Agents--adverse effects; Antiprotozoal Agents--pharmacology; Cell Line; Computational Biology; Drug Evaluation, Preclinical; High-Throughput Screening Assays--methods; Humans; Leishmania major--drug effects; Leishmania major--growth & development; Leishmaniasis, Cutaneous--drug therapy; Leishmaniasis, Cutaneous--parasitology; Parasitic Sensitivity Tests--methods; Small Molecule Libraries--adverse effects; Small Molecule Libraries--pharmacology
Other ID: NLM PMC2765639
PubMed Central ID: PMC2765639
PubMed ID: 19888337
Date Deposited: 03 Aug 2012 16:34
Last Modified: 23 Jun 2018 13:55
URI: http://d-scholarship.pitt.edu/id/eprint/13282

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