5IZC

Trypanosoma brucei PTR1 in complex with inhibitor F032

Summary for 5IZC

• Entry DOI: 10.2210/pdb5izc/pdb
• Descriptor: Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, N~2~-[(thiophen-2-yl)methyl]-1,3,4-thiadiazole-2,5-diamine, ... (7 entities in total)
• Functional Keywords: trypanosoma brucei, pteridine reductase, inhibitor, oxidoreductase
• Biological source: Trypanosoma brucei brucei; More
• Total number of polymer chains: 4
• Total formula weight: 118438.26

Authors

Pozzi, C.,Landi, G.,Di Pisa, F.,Mangani, S. (deposition date: 2016-03-25, release date: 2017-04-05, Last modification date: 2024-01-10)

Primary citation

Linciano, P.,Dawson, A.,Pohner, I.,Costa, D.M.,Sa, M.S.,Cordeiro-da-Silva, A.,Luciani, R.,Gul, S.,Witt, G.,Ellinger, B.,Kuzikov, M.,Gribbon, P.,Reinshagen, J.,Wolf, M.,Behrens, B.,Hannaert, V.,Michels, P.A.M.,Nerini, E.,Pozzi, C.,di Pisa, F.,Landi, G.,Santarem, N.,Ferrari, S.,Saxena, P.,Lazzari, S.,Cannazza, G.,Freitas-Junior, L.H.,Moraes, C.B.,Pascoalino, B.S.,Alcantara, L.M.,Bertolacini, C.P.,Fontana, V.,Wittig, U.,Muller, W.,Wade, R.C.,Hunter, W.N.,Mangani, S.,Costantino, L.,Costi, M.P.
Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery.
ACS Omega, 2:5666-5683, 2017

PubMed Abstract: Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of PTR1 for activity against (). We solved crystal structures of several PTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of PTR1 with low toxicity. In particular, compound , a biphenyl-thiadiazole-2,5-diamine with IC = 16 μM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC value. In addition, the antiparasitic activity of the combination of and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti- agents can be obtained.

PubMed: 28983525
DOI: 10.1021/acsomega.7b00473

Experimental method

X-RAY DIFFRACTION (1.92 Å)