AI Article Synopsis
- Current toxoplasmosis treatments focus on inhibiting dihydrofolate reductase (DHFR) in the parasite, with pyrimethamine being the most common but having toxic side effects due to similar binding sites in humans.
- Computational analysis led to the creation of TRC-19, a new inhibitor that shows significantly better potency (IC of 9 nM) and selectivity (89-fold) for the parasite's DHFR compared to human DHFR.
- Overall, 50% of the newly designed inhibitors met criteria for effectiveness, demonstrating the success of the structure-based drug design method employed in this research.
Article 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 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 IC of 9 nM and 89-fold selectivity in favor of DHFR, as well as crystallographic data to substantiate methodology. Overall, 50% of synthesized designs met hit threshold criteria of IC < 10 μM and >2-fold selectivity favoring , further demonstrating the efficiency of our structure-based drug design approach.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5150685 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.6b00328 | DOI Listing |
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