期刊
EXPERT OPINION ON DRUG DISCOVERY
卷 17, 期 9, 页码 1029-1045出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/17460441.2022.2113776
关键词
Dihydrofolate reductase; folate pathway; molecular docking; molecular dynamics; pteridine reductase 1; structure-based drug design; trypanosomatids; virtual screening
资金
- European Union [603240]
- Klaus Tschira Foundation
- Polish National Science Centre [2016/21/D/NZ1/02806]
- BIOMS program at the Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University
- Jane and Aatos Erkko Foundation
This article reviews the application of structure-based drug design approaches in discovering anti-Trypanosomatid compounds. Although some progress has been made, our incomplete understanding of parasite biology and biochemistry is currently hindering the discovery of selective anti-parasitic drugs.
Introduction Trypanosomatidic parasitic infections in humans and animals caused by Trypanosoma brucei, Trypanosoma cruzi, and Leishmania species pose a significant health and economic burden in developing countries. There are few effective and accessible treatments for these diseases, and the existing therapies suffer from problems, such as parasite resistance and side effects. Structure-based drug design (SBDD) is one of the strategies that has been applied to discover new compounds targeting trypanosomatid-borne diseases. Areas covered We review the current literature (mostly over the last 5 years, searched in the PubMed database on 11 November 2021) on the application of structure-based drug design approaches to identify new anti-trypanosomatidic compounds that interfere with a validated target biochemical pathway, the trypanosomatid folate pathway. Expert opinion The application of structure-based drug design approaches to perturb the trypanosomatid folate pathway has successfully provided many new inhibitors with good selectivity profiles, most of which are natural products or their derivatives or have scaffolds of known drugs. However, the inhibitory effect against the target protein(s) often does not translate to anti-parasitic activity. Further progress is hampered by our incomplete understanding of parasite biology and biochemistry, which is necessary to complement SBDD in a multiparameter optimization approach to discovering selective anti-parasitic drugs.
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