5L42

Leishmania major Pteridine reductase 1 (PTR1) in complex with compound 3

Summary for 5L42

• Entry DOI: 10.2210/pdb5l42/pdb
• Descriptor: Pteridine reductase 1, (2~{R})-2-[3,4-bis(oxidanyl)phenyl]-6-oxidanyl-2,3-dihydrochromen-4-one, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (8 entities in total)
• Functional Keywords: leishmania major, pteridine reductase 1, ptr1, oxidoreductase
• Biological source: Leishmania major
• Total number of polymer chains: 4
• Total formula weight: 127146.27

Authors

Dello Iacono, L.,Di Pisa, F.,Pozzi, C.,Landi, G.,Mangani, S. (deposition date: 2016-05-24, release date: 2017-05-03, Last modification date: 2024-01-10)

Primary citation

Di Pisa, F.,Landi, G.,Dello Iacono, L.,Pozzi, C.,Borsari, C.,Ferrari, S.,Santucci, M.,Santarem, N.,Cordeiro-da-Silva, A.,Moraes, C.B.,Alcantara, L.M.,Fontana, V.,Freitas-Junior, L.H.,Gul, S.,Kuzikov, M.,Behrens, B.,Pohner, I.,Wade, R.C.,Costi, M.P.,Mangani, S.
Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity.
Molecules, 22:-, 2017

PubMed Abstract: Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (-) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes ( PTR1-PTR1 and PTR1) and parasites ( and ). A crystal structure of PTR1 in complex with compound and the first crystal structures of PTR1-flavanone complexes (compounds and ) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.

PubMed: 28282886
DOI: 10.3390/molecules22030426

Experimental method

X-RAY DIFFRACTION (2.1 Å)