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.

Pöhner, I., Quotadamo, A., Panecka-Hofman, J., Luciani, R., Santucci, M., Linciano, P., et al. (2022). Multitarget, selective compound design yields potent inhibitors of a Kinetoplastid Pteridine Reductase 1. JOURNAL OF MEDICINAL CHEMISTRY, 65(13), 9011-9033 [10.1021/acs.jmedchem.2c00232].

Multitarget, selective compound design yields potent inhibitors of a Kinetoplastid Pteridine Reductase 1

Landi, Giacomo;Di Pisa, Flavio;Dello Iacono, Lucia;Pozzi, Cecilia;Mangani, Stefano;
2022-01-01

Abstract

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.
2022
Pöhner, I., Quotadamo, A., Panecka-Hofman, J., Luciani, R., Santucci, M., Linciano, P., et al. (2022). Multitarget, selective compound design yields potent inhibitors of a Kinetoplastid Pteridine Reductase 1. JOURNAL OF MEDICINAL CHEMISTRY, 65(13), 9011-9033 [10.1021/acs.jmedchem.2c00232].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1221114