期刊
FUTURE MEDICINAL CHEMISTRY
卷 13, 期 1, 页码 25-44出版社
FUTURE SCI LTD
DOI: 10.4155/fmc-2020-0057
关键词
cathepsin L; cruzain; cysteine proteases; fluorine; LmCPB; nonpeptidic; structure– activity relationship (SAR)
资金
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/18009-4]
- National Council for Scientific and Technological Development (CNPq) [304030/2018-0]
- FAPESP [2018/03279-0, 2018/03985-1]
- CNPq [142422/2016-9, 130828/2019-0]
- CAPES Drug Discovery program [139/2015]
Through the study of a series of compounds, it was found that these compounds had increased affinity for multiple enzymes, with one compound showing a 60-fold increase in activity against cruzain, and possibly a different mode of binding.
Aim: Compounds that block enzyme activity can kill pathogens and help develop effective and safe drugs for Chagas disease and leishmaniasis. Materials & methods: A library of nonpeptidic nitrile-based compounds was synthesized and had their inhibitory affinity tested against cruzain, Leishmania mexicana cysteine protease B and cathepsin L. Isothermal titration calorimetry experiments and molecular simulations were performed for selected compounds to obtain thermodynamic fingerprints and identify main interactions and putative modes of binding with cruzain. Results: The derivatives provided increased affinity against all enzymes compared with the lead, and thermodynamic and computational studies showed improved thermodynamic properties and a possible different mode of binding. Conclusion: Our studies culminated in 1b, a compound 60-fold more potent in cruzain than its lead that also showed entropic and enthalpic contributions favorable to Gibbs binding energy.
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