Drug Design, Development and Therapy (May 2020)
Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma
Abstract
Ying-Qi Feng,1,* Shuang-Xi Gu,1,* Yong-Shou Chen,1,* Xu-Dong Gao,2 Yi-Xin Ren,1 Jian-Chao Chen,3 Yin-Ying Lu,2 Heng Zhang,1 Shuang Cao1,4 1Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430072, People’s Republic of China; 2Comprehensive Liver Cancer Department, The Fifth Medical Center, Chinese PLA General Hospital, Beijing 100039, People’s Republic of China; 3Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, Shenyang 110016, People’s Republic of China; 4National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuang Cao; Heng ZhangKey Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430072, People’s Republic of ChinaTel/ Fax +86-18701418117; +86-15994288097Email [email protected]; [email protected]: Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC.Methods: A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K. The radiosensitizing effect of the optimized compound ( 2a) was confirmed by colony formation assays and DNA double-strand break assays in vitro. The discovery and preclinical characteristics of this compound are described.Results: The key amino acid residues in mTOR were identified, and a precise virtual screening model was constructed. Compound 2a, with a 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine scaffold, exhibited promising potency against mTOR (mTOR IC50=7.1 nmol/L (nM)) with 126-fold selectivity over PI3Kα. Moreover, 2a significantly enhanced the sensitivity of HCC to radiotherapy in vitro in a dose-dependent manner.Conclusion: A new class of selective mTOR inhibitors was developed and their radiosensitization effects were confirmed. This study also provides a basis for developing mTOR-specific inhibitors for use as radiosensitizers for HCC radiotherapy.Keywords: virtual docking, HCC, kinase inhibitor, mTOR, radiosensitizer
