Publication: Structural Insight into Effective Inhibitors' Binding to Toxoplasma gondii Dihydrofolate Reductase Thymidylate Synthase
Issued Date
2021-01-01
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15548937
15548929
15548929
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2-s2.0-85133963490
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Mahidol University
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SCOPUS
Bibliographic Citation
ACS Chemical Biology. (2021)
Suggested Citation
Jarunee Vanichtanankul, Aphisit Yoomuang, Supannee Taweechai, Thanaya Saeyang, Jutharat Pengon, Jirundon Yuvaniyama, Bongkoch Tarnchompoo, Yongyuth Yuthavong, Sumalee Kamchonwongpaisan Structural Insight into Effective Inhibitors' Binding to Toxoplasma gondii Dihydrofolate Reductase Thymidylate Synthase. ACS Chemical Biology. (2021). doi:10.1021/acschembio.1c00627 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/76311
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Title
Structural Insight into Effective Inhibitors' Binding to Toxoplasma gondii Dihydrofolate Reductase Thymidylate Synthase
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Abstract
Pyrimethamine (Pyr), a known dihydrofolate reductase (DHFR) inhibitor, has long been used to treat toxoplasmosis caused by Toxoplasma gondii (Tg) infection. However, Pyr is effective only at high doses with associated toxicity to patients, calling for safer alternative treatments. In this study, we investigated a series of Pyr analogues, previously developed as DHFR inhibitors of Plasmodium falciparum bifunctional DHFR-thymidylate synthase (PfDHFR-TS), for their activity against T. gondii DHFR-TS (TgDHFR-TS). Of these, a set of compounds with a substitution at the C6 position of the pyrimidine ring exhibited high binding affinities (in a low nanomolar range) against TgDHFR-TS and in vitro T. gondii inhibitory activity. Three-dimensional structures of TgDHFR-TS reported here include the ternary complexes with Pyr, P39, or P40. A comparison of these structures showed the minor steric strain between the p-chlorophenyl group of Pyr and Thr83 of TgDHFR-TS. Such a conflict was relieved in the complexes with the two analogues, P39 and P40, explaining their highest binding affinities described herein. Moreover, these structures suggested that the hydrophobic environment in the active-site pocket could be used for drug design to increase the potency and selectivity of antifolate inhibitors. These findings would accelerate the development of new antifolate drugs to treat toxoplasmosis.