Identification and New Indication of Melanin-Concentrating Hormone Receptor 1 (MCHR1) Antagonist Derived from Machine Learning and Transcriptome-Based Drug Repositioning Approaches

International Journal of Molecular Sciences

Moon Kook Jeon¹  Jeong Hyun Lee¹  Ka Young You¹  Gyutae Lim¹  Byung Ho Lee¹  Kwang-Seok Oh¹  Jae Yong Ryu² 

[1] Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea;Department of Biotechnology, Duksung Women’s University, 33 Samyang-ro 144-gil, Dobong-gu, Seoul 01369, Korea;

关键词: melanin-concentrating hormone;    MCHR1 antagonists;    obesity;    cardiotoxicity;    hERG;    machine learning model;   

DOI  :  10.3390/ijms23073807

来源: DOAJ

【 摘 要 】

Melanin-concentrating hormone receptor 1 (MCHR1) has been a target for appetite suppressants, which are helpful in treating obesity. However, it is challenging to develop an MCHR1 antagonist because its binding site is similar to that of the human Ether-à-go-go-Related Gene (hERG) channel, whose inhibition may cause cardiotoxicity. Most drugs developed as MCHR1 antagonists have failed in clinical development due to cardiotoxicity caused by hERG inhibition. Machine learning-based prediction models can overcome these difficulties and provide new opportunities for drug discovery. In this study, we identified KRX-104130 with potent MCHR1 antagonistic activity and no cardiotoxicity through virtual screening using two MCHR1 binding affinity prediction models and an hERG-induced cardiotoxicity prediction model. In addition, we explored other possibilities for expanding the new indications for KRX-104130 using a transcriptome-based drug repositioning approach. KRX-104130 increased the expression of low-density lipoprotein receptor (LDLR), which induced cholesterol reduction in the gene expression analysis. This was confirmed by comparison with gene expression in a nonalcoholic steatohepatitis (NASH) patient group. In a NASH mouse model, the administration of KRX-104130 showed a protective effect by reducing hepatic lipid accumulation, liver injury, and histopathological changes, indicating a promising prospect for the therapeutic effect of NASH as a new indication for MCHR1 antagonists.

【 授权许可】

Unknown