Abstract:
:Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and human DHFR. Computational analysis of biochemical differences between Toxoplasma gondii and human DHFR enabled the design of inhibitors with both improved potency and selectivity. The approach described herein yielded TRC-19, a promising lead with an IC50 of 9 nM and 89-fold selectivity in favor of Toxoplasma gondii DHFR, as well as crystallographic data to substantiate in silico methodology. Overall, 50% of synthesized in silico designs met hit threshold criteria of IC50 < 10 μM and >2-fold selectivity favoring Toxoplasma gondii, further demonstrating the efficiency of our structure-based drug design approach.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Welsch ME,Zhou J,Gao Y,Yan Y,Porter G,Agnihotri G,Li Y,Lu H,Chen Z,Thomas SBdoi
10.1021/acsmedchemlett.6b00328subject
Has Abstractpub_date
2016-09-17 00:00:00pages
1124-1129issue
12issn
1948-5875journal_volume
7pub_type
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