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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

Texto completo
Autor(es):
Kimani, Njogu M. [1] ; Matasyoh, Josphat C. [2] ; Kaiser, Marcel [3, 4] ; Nogueira, Mauro S. [1] ; Trossini, Gustavo H. G. [5] ; Schmidt, Thomas J. [1]
Número total de Autores: 6
Afiliação do(s) autor(es):
[1] Univ Munster, IPBP, PharmaCampus, Corrensstr 48, D-48149 Munster - Germany
[2] Egerton Univ, Dept Chem, POB 536, Egerton 20115 - Kenya
[3] Swiss TPH, Swiss Trop & Publ Hlth Inst, Socinstr 57, CH-4051 Basel - Switzerland
[4] Univ Basel, Peterspl 1, CH-4003 Basel - Switzerland
[5] Univ Sao Paulo, Fac Ciencias Farmaceut, Av Lineu Prestes 580, BR-05508000 Sao Paulo - Brazil
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 19, n. 12 DEC 2018.
Citações Web of Science: 3
Resumo

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 (R-2) ranging from 0.71 to 0.85, as well as internal (leave-one-out Q(2) values ranging from 0.62 to 0.72) and external validation coefficients (P-2 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. (AU)

Processo FAPESP: 17/25543-8 - Estratégias de química medicinal (LBDD e SBDD) na busca de inibidores de sirtuína 2 de tripanossomatídeos
Beneficiário:Gustavo Henrique Goulart Trossini
Linha de fomento: Auxílio à Pesquisa - Regular