Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 65, Issue 13, Pages 9011-9033Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00232
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Funding
- 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
- Interdisciplinary Centre for Mathematical and Computational Modelling (ICM) , University of Warsaw [G70-13, GB70-11, GA73-25]
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This study presents a systematic, multidisciplinary approach to the development of selective antiparasitic compounds with multiple targets. The approach combines computational fragment-based design and crystallographic structure determination to derive a structure-activity relationship for multitarget inhibition. The optimized compounds show promising inhibition against various parasitic targets while minimizing toxicity.
The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine deriva-tives along with iterations of crystallographic structure determi-nation allowed for the derivation of a structure-activity relation-ship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC50 values against T. brucei brucei while retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.
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