5JCJ

Trypanosoma brucei PTR1 in complex with inhibitor NMT-H037 (compound 7)

Summary for 5JCJ

• Entry DOI: 10.2210/pdb5jcj/pdb
• Descriptor: Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ACETATE ION, ... (6 entities in total)
• Functional Keywords: trypanosoma brucei, pteridine reductase, oxydoreductase, inhibitor, oxidoreductase
• Biological source: Trypanosoma brucei brucei; More
• Total number of polymer chains: 4
• Total formula weight: 126645.58

Authors

Landi, G.,Pozzi, C.,Di Pisa, F.,Dello Iacono, L.,Mangani, S. (deposition date: 2016-04-15, release date: 2016-08-17, Last modification date: 2024-01-10)

Primary citation

Borsari, C.,Luciani, R.,Pozzi, C.,Poehner, I.,Henrich, S.,Trande, M.,Cordeiro-da-Silva, A.,Santarem, N.,Baptista, C.,Tait, A.,Di Pisa, F.,Dello Iacono, L.,Landi, G.,Gul, S.,Wolf, M.,Kuzikov, M.,Ellinger, B.,Reinshagen, J.,Witt, G.,Gribbon, P.,Kohler, M.,Keminer, O.,Behrens, B.,Costantino, L.,Tejera Nevado, P.,Bifeld, E.,Eick, J.,Clos, J.,Torrado, J.,Jimenez-Anton, M.D.,Corral, M.J.,Alunda, J.M.,Pellati, F.,Wade, R.C.,Ferrari, S.,Mangani, S.,Costi, M.P.
Profiling of Flavonol Derivatives for the Development of Antitrypanosomatidic Drugs.
J.Med.Chem., 59:7598-7616, 2016

PubMed Abstract: Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from a library of natural products, we combined target-based screening on pteridine reductase 1 with phenotypic screening on Trypanosoma brucei for hit identification. Flavonols were identified as hits, and a library of 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. brucei below 10 μM. Four X-ray crystal structures and docking studies explained the observed structure-activity relationships. Compound 2 (3,6-dihydroxy-2-(3-hydroxyphenyl)-4H-chromen-4-one) was selected for pharmacokinetic studies. Encapsulation of compound 2 in PLGA nanoparticles or cyclodextrins resulted in lower in vitro toxicity when compared to the free compound. Combination studies with methotrexate revealed that compound 13 (3-hydroxy-6-methoxy-2-(4-methoxyphenyl)-4H-chromen-4-one) has the highest synergistic effect at concentration of 1.3 μM, 11.7-fold dose reduction index and no toxicity toward host cells. Our results provide the basis for further chemical modifications aimed at identifying novel antitrypanosomatidic agents showing higher potency toward PTR1 and increased metabolic stability.

PubMed: 27411733
DOI: 10.1021/acs.jmedchem.6b00698

Experimental method

X-RAY DIFFRACTION (1.76 Å)