title: Discovery of Potent and Selective Leads againstToxoplasma gondiiDihydrofolate Reductase via Structure-Based Design.
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 betweenToxoplasma gondiiand 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 IC50of 9 nM and 89-fold selectivity in favor ofToxoplasma gondiiDHFR, as well as crystallographic data to substantiatein silicomethodology. Overall, 50% of synthesizedin silicodesigns met hit threshold criteria of IC50< 10 μM and >2-fold selectivity favoringToxoplasma gondii, further demonstrating the efficiency of our structure-based drug design approach.
authors.affiliation: Turing Pharmaceuticals AG , Research & Development, 1177 Avenue of the Americas, 39th Floor, New York, New York 10036, United States.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Welsch
authors.affiliation: WuXi AppTec , International Discovery Service Unit & Research Service Division, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: WuXi AppTec , International Discovery Service Unit & Research Service Division, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Yueqiang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: WuXi AppTec , International Discovery Service Unit & Research Service Division, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Yan
authors.affiliation: WuXi AppTec , In Vitro Biology US, 107 Morgan Lane, Plainsborough, New Jersey 08536, United States.
authors.forename: Gene
authors.initials: G
authors.lastname: Porter
authors.affiliation: WuXi AppTec , In Vitro Biology US, 107 Morgan Lane, Plainsborough, New Jersey 08536, United States.
authors.forename: Gautam
authors.initials: G
authors.lastname: Agnihotri
authors.affiliation: WuXi AppTec , International Discovery Service Unit & Research Service Division, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Li
authors.affiliation: WuXi AppTec , International Discovery Service Unit & Research Service Division, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Henry
authors.initials: H
authors.lastname: Lu
authors.affiliation: WuXi AppTec , International Discovery Service Unit & Research Service Division, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Turing Pharmaceuticals AG , Research & Development, 1177 Avenue of the Americas, 39th Floor, New York, New York 10036, United States.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Thomas
keywords: DHFR inhibitor; Toxoplasmosis; in silico screening; molecular modeling