Molecular modeling study of the thymidine phosphorylase inhibitor by SBDD and classical QSAR analysis

Chem-Bio Informatics Journal

Shingo Yano¹  Yukio Tada²  Tsutomu Sato³  Tomohiro Emura³  Hideki Kazuno³  Norihiko Suzuki³ 

[1] CMC Center, Taiho Pharmaceutical Co., Ltd.;Department of Computational Intelligence and System Science, Tokyo Institute of Technology;Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd.

关键词: thymidine phosphorylase;    チミジンホスホリラーゼ;    thymidine phosphorylase inhibitor;    チミジンホスホリラーゼ阻害薬;    trifluorothymine;    トリフルオロチミジン;    SBDD;    classical QSAR;   

DOI  :  10.1273/cbij.17.19

学科分类：生物化学/生物物理

来源: Chem-Bio Informatics Society

【 摘 要 】

Trifluorothymidine (TFT) has antitumor activity, but it is easily metabolized to inert trifluorothymine by thymidine phosphorylase (TP). Accordingly, TFT alone cannot show satisfactory clinical antitumor effects. Human TP (HTP) is the main enzyme of pyrimidine nucleoside phosphorylase in human. Therefore, it has been necessary to develop a HTP inhibitor to maintain antitumor activity of TFT. Here we reveal the drug design process of HTP inhibitor based on SBDD and classical QSAR analysis. Thymine was selected as a seed compound and then 5-chlorouracil (3) was selected as a lead compound. The introduction of the imino moiety to C6 position of the lead compound (3) enhanced the inhibitory activity of TP. As a result, 5-chloro-6-[1-(2-iminopyrrolidinyl) methyl] uracil hydrochloride (TPI) was chosen as the candidate for the clinical trials. And TAS-102 (the combination of TFT and TPI in a 10.5 molar ratio) has been approved as Trifluridine/Tipiracil (Lonsurf) for the treatment of metastatic colorectal cancer in Japan, United States and EU.

【 授权许可】

CC BY