6N1S

Toxoplasma gondii TS-DHFR in complex with selective inhibitor 29

Summary for 6N1S

• Entry DOI: 10.2210/pdb6n1s/pdb
• Related: 4eil 6aog 6aoh 6aoi 6n1t
• Descriptor: Bifunctional dihydrofolate reductase-thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• Functional Keywords: toxoplasma gondii, dhfr, oxidoreductase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Toxoplasma gondii
• Total number of polymer chains: 2
• Total formula weight: 132277.70

Authors

Hopper, A.T.,Brockman, A.,Wise, A.,Gould, J.,Barks, J.,Radke, J.B.,Sibley, L.D.,Zou, Y.,Thomas, S.B. (deposition date: 2018-11-11, release date: 2019-01-23, Last modification date: 2023-10-11)

Primary citation

Hopper, A.T.,Brockman, A.,Wise, A.,Gould, J.,Barks, J.,Radke, J.B.,Sibley, L.D.,Zou, Y.,Thomas, S.
Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis.
J. Med. Chem., 62:1562-1576, 2019

PubMed Abstract: A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC of 1.57 ± 0.11 nM and a hDHFR to TgDHFR selectivity ratio of 196, making it 89-fold more potent and 16-fold more selective than 1. Compound 3 was highly effective in control of acute infection by highly virulent strains of T. gondii in the murine model, and it possesses the best combination of selectivity, potency, and prerequisite drug-like properties to advance into IND-enabling, preclinical development.

PubMed: 30624926
DOI: 10.1021/acs.jmedchem.8b01754

Experimental method

X-RAY DIFFRACTION (3 Å)