期刊
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
卷 90, 期 -, 页码 180-191出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmgm.2019.04.007
关键词
QSAR; HQSAR; Random forest; Machine learning techniques; Nitroimidazoles derivatives; Metronidazole-resistant Trichomonas vaginalis
类别
资金
- CNPq [456984/2014-3]
- CAPES
- OpenEye Scientific Software for OMEGA
Trichomonas vaginalis is the causative agent of trichomoniasis, a highly prevalent sexually transmitted infection worldwide. Nitroimidazole drugs, such as metronidazole and tinidazole, are the only recommended treatment, but cases of resistance represent at least 5%. In case of resistance or therapeutic failure, posology with higher doses is used, culminating in the increase of the toxic effects of the treatment. In this context, the development of new drugs becomes an eminent necessity. Hologram quantitative structure-activity relationship (HQSAR) models using nitroimidazole derivatives were generated to discover the relationship between the different chemical structures and the activity against cells and the selectivity against susceptible and resistant strains. One model of each strain was chosen for interpretation, both showed good internal coefficient (q(LOO)(2) values: 0.607 for susceptible strain and 0.646 for resistant strain subsets) and great values in other internal and external validations metrics. From the contribution of fragments to HQSAR models, several differences between the most and least potent compounds were found: 5-nitroimidazole contributes positively while 4-nitroimidazole negatively. QSAR models employing random forest (RF-QSAR) machine learning technique were also built and a robust model was obtained from resistant strain activity prediction (q(LOO)(2) equals to 0.618). The constructed HQSAR and RF-QSAR models were employed to predict the activity of three newly planned nitroimidazole derivatives in the design of new drugs candidates against T. vaginalis strains. (C) 2019 Elsevier Inc. All rights reserved.
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