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Design and Structure-Based Study of New Potential FKBP12 Inhibitors

Fei Sun ^* ¶, Pengyun Li ^*, Yi Ding ^*, Liwei Wang ^*, Mark Bartlam ^*, Cuilin Shu , Beifen Shen , Hualiang Jiang , Song Li  and Zihe Rao ^* ¶

^* Laboratory of Structural Biology and Ministry of Education Laboratory of Protein Science, Tsinghua University, Beijing, China; Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing, China; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing, China; and ^¶ National Laboratory of Biological Macromolecules and Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

Correspondence: Address reprint requests to Zihe Rao, Laboratory of Structural Biology, School of Life Science and Engineering, Tsinghua University, Beijing 100084, China. Tel: 86-106-277-1493; Fax: 86-106-277-3145; E-mail: raozh{at}xtal.tsinghua.edu.cn; or Song Li, Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China. Tel.: 86-106-693-1250; Fax: 86-106-821-4653; E-mail: lis{at}nic.bmi.ac.cn.

Based on the structure of FKBP12 complexed with FK506 or rapamycin, with computer-aided design, two neurotrophic ligands, (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-Leucine ethyl ester and (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-phenylalanine benzyl ester, were designed and synthesized. Fluorescence experiments were used to detect the binding affinity between FKBP12 and these two ligands. Complex structures of FKBP12 with these two ligands were obtained by x-ray crystallography. In comparing FKBP12-rapamycin complex and FKBP12-FK506 complex as well as FKBP12-GPI-1046 solution structure with these new complexes, significant volume and surface area effects and obvious contact changes were detected which are expected to cause their different binding energies—showing these two novel ligands will become more effective neuron regeneration drugs than GPI-1046, which is currently undergoing phase II clinical trail as a neurotrophic drug. Analysis of volume and surface area effects also gives a new clue for structure-based drug design.