Multitarget, selective compound design yields potent inhibitors of a kinetoplastid pteridine reductase 1

DOI: 10.1021/acs.jmedchem.2c00232

Authors: Ina Pöhner (Heidelberg Institute for Theoretical Studies (HITS); Heidelberg University) , Antonio Quotadamo (Tydock Pharma srl; University of Modena and Reggio Emilia) , Joanna Panecka-Hofman (Heidelberg Institute for Theoretical Studies (HITS); University of Warsaw) , Rosaria Luciani (University of Modena and Reggio Emilia) , Matteo Santucci (University of Modena and Reggio Emilia) , Pasquale Linciano (University of Modena and Reggio Emilia) , Giacomo Landi (University of Siena) , Flavio Di Pisa (University of Siena) , Lucia Dello Iacono (University of Siena) , Cecilia Pozzi (University of Siena) , Stefano Mangani (University of Siena) , Sheraz Gul (Fraunhofer Institute for Translational Medicine and Pharmacology ITMP) , Gesa Witt (Fraunhofer Institute for Translational Medicine and Pharmacology ITMP) , Bernhard Ellinger (Fraunhofer Institute for Translational Medicine and Pharmacology ITMP) , Maria Kuzikov (Fraunhofer Institute for Translational Medicine and Pharmacology ITMP) , Nuno Santarem (Universidade do Porto) , Anabela Cordeiro-Da-Silva (Universidade do Porto) , Maria P. Costi (University of Modena and Reggio Emilia) , Alberto Venturelli (University of Modena and Reggio Emilia) , Rebecca C. Wade (Heidelberg Institute for Theoretical Studies (HITS); Heidelberg University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 51

State: Published (Approved)
Published: June 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.

Journal Keywords: Inhibition; Inhibitors; Parasites; Reaction products; Selectivity

Diamond Keywords: Sleeping Sickness; Leishmaniasis; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 09/06/2022 14:42

Discipline Tags:

Infectious Diseases Disease in the Developing World Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)