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 derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure-activity relationship 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.

Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1 / Pohner, I.; Quotadamo, A.; Panecka-Hofman, J.; Luciani, R.; Santucci, M.; Linciano, P.; Landi, G.; Di Pisa, F.; Dello Iacono, L.; Pozzi, C.; Mangani, S.; Gul, S.; Witt, G.; Ellinger, B.; Kuzikov, M.; Santarem, N.; Cordeiro-Da-Silva, A.; Costi, M. P.; Venturelli, A.; Wade, R. C.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 65:13(2022), pp. 9011-9033. [10.1021/acs.jmedchem.2c00232]

Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1

Costi M. P.;Venturelli A.;
2022

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 derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure-activity relationship 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
65
13
9011
9033
Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1 / Pohner, I.; Quotadamo, A.; Panecka-Hofman, J.; Luciani, R.; Santucci, M.; Linciano, P.; Landi, G.; Di Pisa, F.; Dello Iacono, L.; Pozzi, C.; Mangani, S.; Gul, S.; Witt, G.; Ellinger, B.; Kuzikov, M.; Santarem, N.; Cordeiro-Da-Silva, A.; Costi, M. P.; Venturelli, A.; Wade, R. C.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 65:13(2022), pp. 9011-9033. [10.1021/acs.jmedchem.2c00232]
Pohner, I.; Quotadamo, A.; Panecka-Hofman, J.; Luciani, R.; Santucci, M.; Linciano, P.; Landi, G.; Di Pisa, F.; Dello Iacono, L.; Pozzi, C.; Mangani, S.; Gul, S.; Witt, G.; Ellinger, B.; Kuzikov, M.; Santarem, N.; Cordeiro-Da-Silva, A.; Costi, M. P.; Venturelli, A.; Wade, R. C.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1287326
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