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Article

Complementary Quantitative Structure–Activity Relationship Models for the Antitrypanosomal Activity of Sesquiterpene Lactones

1
Institute of Pharmaceutical Biology and Phytochemistry (IPBP), University of Muenster, PharmaCampus Corrensstrasse 48, D-48149 Muenster, Germany
2
Department of Chemistry, Egerton University, P.O. Box 536, Egerton 20115, Kenya
3
Swiss Tropical and Public Health Institute (Swiss TPH), Socinstrasse 57, CH-4051 Basel, Switzerland
4
University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland
5
Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Av. Lineu Prestes 580, 05508-000 São Paulo, Brazil
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(12), 3721; https://doi.org/10.3390/ijms19123721
Received: 5 October 2018 / Revised: 17 November 2018 / Accepted: 19 November 2018 / Published: 22 November 2018
(This article belongs to the Section Molecular Informatics)
Three complementary quantitative structure–activity relationship (QSAR) methodologies, namely, regression modeling based on (i) “classical” molecular descriptors, (ii) 3D pharmacophore features, and (iii) 2D molecular holograms (HQSAR) were employed on the antitrypanosomal activity of sesquiterpene lactones (STLs) toward Trypanosoma brucei rhodesiense (Tbr), the causative agent of the East African form of human African trypanosomiasis. In this study, an extension of a previous QSAR study on 69 STLs, models for a much larger and more diverse set of such natural products, now comprising 130 STLs of various structural subclasses, were established. The extended data set comprises a variety of STLs isolated and tested for antitrypanosomal activity within our group and is furthermore enhanced by 12 compounds obtained from literature, which have been tested in the same laboratory under identical conditions. Detailed QSAR analyses yielded models with comparable and good internal and external predictive ability. For a set of compounds as chemically diverse as the one under study, the models exhibited good coefficients of determination (R2) ranging from 0.71 to 0.85, as well as internal (leave-one-out Q2 values ranging from 0.62 to 0.72) and external validation coefficients (P2 values ranging from 0.54 to 0.73). The contributions of the various tested descriptors to the generated models are in good agreement with the results of previous QSAR studies and corroborate the fact that the antitrypanosomal activity of STLs is very much dependent on the presence and relative position of reactive enone groups within the molecular structure but is influenced by their hydrophilic/hydrophobic properties and molecular shape. View Full-Text
Keywords: QSAR; sesquiterpene lactones; Trypanosoma brucei; human African trypanosomiasis; pharmacophore-based drug design QSAR; sesquiterpene lactones; Trypanosoma brucei; human African trypanosomiasis; pharmacophore-based drug design
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MDPI and ACS Style

Kimani, N.M.; Matasyoh, J.C.; Kaiser, M.; Nogueira, M.S.; Trossini, G.H.G.; Schmidt, T.J. Complementary Quantitative Structure–Activity Relationship Models for the Antitrypanosomal Activity of Sesquiterpene Lactones. Int. J. Mol. Sci. 2018, 19, 3721. https://doi.org/10.3390/ijms19123721

AMA Style

Kimani NM, Matasyoh JC, Kaiser M, Nogueira MS, Trossini GHG, Schmidt TJ. Complementary Quantitative Structure–Activity Relationship Models for the Antitrypanosomal Activity of Sesquiterpene Lactones. International Journal of Molecular Sciences. 2018; 19(12):3721. https://doi.org/10.3390/ijms19123721

Chicago/Turabian Style

Kimani, Njogu M., Josphat C. Matasyoh, Marcel Kaiser, Mauro S. Nogueira, Gustavo H.G. Trossini, and Thomas J. Schmidt. 2018. "Complementary Quantitative Structure–Activity Relationship Models for the Antitrypanosomal Activity of Sesquiterpene Lactones" International Journal of Molecular Sciences 19, no. 12: 3721. https://doi.org/10.3390/ijms19123721

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