Multitarget, Selective Compound Design Yields Picomolar Inhibitors of a Kinetoplastid Pteridine Reductase 1
Year: 2020
Type: preprint
Abstract: The optimization of compounds with multiple targets in the drug discovery cycle is a difficult multidimensional problem. Here, we present a systematic, multidisciplinary approach to the development of selective anti-parasitic compounds. Efficient microwave-assisted synthesis of pteridines along with iterations of crystallographic structure determination were used to validate computational docking predictions and support derivation of a structure-activity relationship for multitarget inhibition. This approach yielded compounds showing picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, along with selective submicromolar inhibition of parasitic dihydrofolate reductase (DHFR). Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC 50 values against T. brucei brucei , whilst 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.
Source: ChemRxiv
Authors: Ina Poehner, Antonio Quotadamo, Joanna Panecka-Hofman, Rosaria Luciani, Matteo Santucci, Pasquale Linciano, Giacomo Landi, Flavio Di Pisa, Lucia Dello Iacono, Cecilia Pozzi, Stefano Mangani, Sheraz Gul, Gesa Witt, Bernhard Ellinger, Maria Kuzikov, Nuno Santarem, Anabela Cordeiro-da-Silva, Maria Paola Costi, Alberto Venturelli, Rebecca Wade
Institutions: Heidelberg Institute for Theoretical Studies, University of Modena and Reggio Emilia, Tydock Pharma (Italy), University of Warsaw, University of Siena, Fraunhofer Institute for Molecular Biology and Applied Ecology, Universidade do Porto, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Instituto de Biologia Molecular e Celular, Heidelberg University, DKFZ-ZMBH Alliance
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4240700726