کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1393127 | 1501182 | 2010 | 11 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery Novel insights for dihydroorotate dehydrogenase class 1A inhibitors discovery](/preview/png/1393127.png)
The enzyme dihydroorotate dehydrogenase (DHODH) has been suggested as a promising target for the design of trypanocidal agents. We report here the discovery of novel inhibitors of Trypanosoma cruzi DHODH identified by a combination of virtual screening and ITC methods. Monitoring of the enzymatic reaction in the presence of selected ligands together with structural information obtained from X-ray crystallography analysis have allowed the identification and validation of a novel site of interaction (S2 site). This has provided important structural insights for the rational design of T. cruzi and Leishmania major DHODH inhibitors. The most potent compound (1) in the investigated series inhibits TcDHODH enzyme with Kiapp value of 19.28 μM and possesses a ligand efficiency of 0.54 kcal mol−1 per non-H atom. The compounds described in this work are promising hits for further development.
Orthogonal validation of ITC nonlinear least squares fit of Michaelis–Menten curves and X-Ray data for 5-aminoorotic acid competitive inhibition. Figure optionsDownload as PowerPoint slide
Journal: European Journal of Medicinal Chemistry - Volume 45, Issue 12, December 2010, Pages 5899–5909