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Seeking mTORC1 Inhibitors Through Molecular Dynamics Simulation of Arginine Analogs Inhibiting CASTOR1.
Sun, Liang; Li, Xinyu; Pan, Jun; Mao, Jiashun; Yuan, Yueyang; Wang, Duoxi; Sun, Weiwei; Krueger, Gerhard R F; Wang, Guanyu.
Afiliação
  • Sun L; Department of Biology, Southern University of Science and Technology, Shenzhen, P.R. China.
  • Li X; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, P.R. China.
  • Pan J; School of Life and Health Sciences and Warshel Institute for Computational Biology, The Chinese University of Hong Kong, Shenzhen, P.R. China.
  • Mao J; Department of Biology, Southern University of Science and Technology, Shenzhen, P.R. China.
  • Yuan Y; Department of Biology, Southern University of Science and Technology, Shenzhen, P.R. China.
  • Wang D; Department of Biology, Southern University of Science and Technology, Shenzhen, P.R. China.
  • Sun W; Guangdong Provincial Key Laboratory of Computational Science and Material Design, Shenzhen, P.R. China.
  • Krueger GRF; Department of Biology, Southern University of Science and Technology, Shenzhen, P.R. China.
  • Wang G; Department of Pathology, Shanghai Songjiang Central Hospital, Shanghai, P.R. China swwmmm@163.com Gerhard.Krueger@uth.tmc.edu wanggy@sustech.edu.cn.
Cancer Genomics Proteomics ; 16(6): 465-479, 2019.
Article em En | MEDLINE | ID: mdl-31659101
BACKGROUND: Hyperactivity of the mechanistic target of rapamycin complex 1 (mTORC1) is implicated in a variety of diseases such as cancer and diabetes. Treatment may benefit from effective mTORC1 inhibition, which can be achieved by preventing arginine from disrupting the cytosolic arginine sensor for mTORC1 subunit 1 (CASTOR1)-GTPase-activating proteins toward RAGS subcomplex 2 (GATOR2) complex through binding with CASTOR1. An attractive idea is to determine analogues of arginine that are as competent as arginine in binding with CASTOR1, but without disrupting the CASTOR1-GATOR2 interaction. MATERIALS AND METHODS: Molecular dynamics simulations were performed for binding of arginine analogues with CASTOR1 and binding free energy, hydrogen bond formation, and root mean squared deviation and root mean square fluctuation kinetics were then calculated. RESULTS: The binding free energy calculations revealed that Nα-acetyl-arginine, citrulline, and norarginine have sufficient binding affinity with CASTOR1 to compete with arginine. The hydrogen bond analysis revealed that norarginine, Nα-acetyl-arginine and D-arginine have proficient H-bonds that can facilitate their entering the narrow binding pocket. CONCLUSION: Norarginine and Nα-acetyl-arginine are the top drug candidates for mTORC1 inhibition, with Nα-acetyl-arginine being the best choice.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Arginina / Citrulina / Peptídeos e Proteínas de Sinalização Intracelular / Simulação de Dinâmica Molecular / Alvo Mecanístico do Complexo 1 de Rapamicina Limite: Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Arginina / Citrulina / Peptídeos e Proteínas de Sinalização Intracelular / Simulação de Dinâmica Molecular / Alvo Mecanístico do Complexo 1 de Rapamicina Limite: Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article