Study of the antimalarial activity of 4-aminoquinoline compounds against chloroquine-sensitive and chloroquine-resistant parasite strains
| Autor: | Alexandre S. Lawrenson, Paul M. O'Neill, David L. Cooper, Neil G. Berry |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Quantitative structure–activity relationship Plasmodium falciparum Drug Resistance Computational biology K1 Biology 01 natural sciences Catalysis Inorganic Chemistry Machine Learning 03 medical and health sciences chemistry.chemical_compound Antimalarials Chloroquine parasitic diseases Partial least squares regression NF54 medicine Food vacuole Parasite hosting Physical and Theoretical Chemistry Original Paper QSAR Organic Chemistry biology.organism_classification 0104 chemical sciences Computer Science Applications Malaria 010404 medicinal & biomolecular chemistry 030104 developmental biology Computational Theory and Mathematics chemistry 4-Aminoquinoline Aminoquinolines medicine.drug |
| Zdroj: | Journal of Molecular Modeling JOURNAL OF MOLECULAR MODELING |
| ISSN: | 0948-5023 1610-2940 |
| Popis: | This study is concerned with identifying features of 4-aminoquinoline scaffolds that can help pinpoint characteristics that enhance activity against chloroquine-resistant parasites. Statistically valid predictive models are reported for a series of 4-aminoquinoline analogues that are active against chloroquine-sensitive (NF54) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Quantitative structure activity relationship techniques, based on statistical and machine learning methods such as multiple linear regression and partial least squares, were used with a novel pruning method for the selection of descriptors to develop robust models for both strains. Inspection of the dominant descriptors supports the hypothesis that chemical features that enable accumulation in the food vacuole of the parasite are key determinants of activity against both strains. The hydrophilic properties of the compounds were found to be crucial in predicting activity against the chloroquine-sensitive NF54 parasite strain, but not in the case of the chloroquine-resistant K1 strain, in line with previous studies. Additionally, the models suggest that ‘softer’ compounds tend to have improved activity for both strains than do ‘harder’ ones. The internally and externally validated models reported here should also prove useful in the future screening of potential antimalarial compounds for targeting chloroquine-resistant strains. Graphical Abstract Predictive models reveal linear relationships for activity of 4-aminoquinoline analogues active against chloroquine-sensitive strains of Plasmodium falciparum Electronic supplementary material The online version of this article (10.1007/s00894-018-3755-z) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink