6RX5
Trypanosoma brucei PTR1 (TbPTR1) in complex with inhibitor 1 (NMT-C0003)
Summary for 6RX5
| Entry DOI | 10.2210/pdb6rx5/pdb |
| Related | 6RX0 |
| Descriptor | Pteridine reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, METHYL 1-(4-{[(2,4-DIAMINOPTERIDIN-6-YL)METHYL](METHYL)AMINO}BENZOYL)PIPERIDINE-4-CARBOXYLATE, ... (6 entities in total) |
| Functional Keywords | trypanosoma brucei, pteridine reductase, ptr1, tbptr1, pteridine based inhibitors, oxidoreductase |
| Biological source | Trypanosoma brucei brucei |
| Total number of polymer chains | 4 |
| Total formula weight | 127155.40 |
| Authors | Landi, G.,Pozzi, C.,Mangani, S. (deposition date: 2019-06-07, release date: 2020-07-15, Last modification date: 2024-01-24) |
| Primary citation | Pohner, I.,Quotadamo, A.,Panecka-Hofman, J.,Luciani, R.,Santucci, M.,Linciano, P.,Landi, G.,Di Pisa, F.,Dello Iacono, L.,Pozzi, C.,Mangani, S.,Gul, S.,Witt, G.,Ellinger, B.,Kuzikov, M.,Santarem, N.,Cordeiro-da-Silva, A.,Costi, M.P.,Venturelli, A.,Wade, R.C. Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1. J.Med.Chem., 65:9011-9033, 2022 Cited by PubMed 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 pteridine reductase 1 (PTR1), nanomolar inhibition of 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 EC values against 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. PubMed: 35675511DOI: 10.1021/acs.jmedchem.2c00232 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.42 Å) |
Structure validation
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