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Identification of novel natural inhibitors targeting AKT Serine/Threonine Kinase 1 (AKT1) by computational study

Despite great progress, the current cancer treatments often have obvious toxicity and side effects. and a poor prognosis (some patients). One of the reasons for the poor prognosis is that certain enzymes prevent anticancer drugs from killing tumor cells. AKT1 is involved in regulating PI3K/AKT/mTOR,...

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Autores principales: Zhong, Sheng, Hou, Yuanyuan, Zhang, Zhiyun, Guo, Zhen, Yang, Wenzhuo, Dou, Gaojing, Lv, Xiaye, Wang, Xinhui, Ge, Junliang, Wu, Bo, Pan, Xuefeng, Wang, Hongyu, Yang, Qunying, Mou, Yonggao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9275969/
https://www.ncbi.nlm.nih.gov/pubmed/35603567
http://dx.doi.org/10.1080/21655979.2021.2011631
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author Zhong, Sheng
Hou, Yuanyuan
Zhang, Zhiyun
Guo, Zhen
Yang, Wenzhuo
Dou, Gaojing
Lv, Xiaye
Wang, Xinhui
Ge, Junliang
Wu, Bo
Pan, Xuefeng
Wang, Hongyu
Yang, Qunying
Mou, Yonggao
author_facet Zhong, Sheng
Hou, Yuanyuan
Zhang, Zhiyun
Guo, Zhen
Yang, Wenzhuo
Dou, Gaojing
Lv, Xiaye
Wang, Xinhui
Ge, Junliang
Wu, Bo
Pan, Xuefeng
Wang, Hongyu
Yang, Qunying
Mou, Yonggao
author_sort Zhong, Sheng
collection PubMed
description Despite great progress, the current cancer treatments often have obvious toxicity and side effects. and a poor prognosis (some patients). One of the reasons for the poor prognosis is that certain enzymes prevent anticancer drugs from killing tumor cells. AKT1 is involved in regulating PI3K/AKT/mTOR, a tumor-generating pathway. Ipatasertib, a highly selective inhibitor of AKT1, is widely used in the treatment of tumors. In this study, many structural and biochemical methodswere used to find better AKT1(Threonine Kinase 1) inhibitors, which laid a foundation for the further development of AKT1 inhibitors and provided new drugs for the treatment of tumors. ZINC15 database and Discovery Studio 4.5, a computer-aided drug screening software with many modules (LibDock for virtual screening, ADME (Absorption, Distribution, Metabolism, Excretion) and TOPKAT (toxicity prediction module) for the toxicity and properties analysis, and MD simulation for stability prediction), were employed. CCK8 assay, ELISA assay genicity and higher tolerance to cytochrome P4502D6. MD simulations indicated they could bind with AKT1 stably in the natural environment. The cell experiment and specific assay for AKT1 inhibition showed they could inhibit the proliferation and AKT1 expression of MG63 cells (Osteosarcoma cells). Moreover, these novel compounds with structural modifications can be potential contributors that lead to further rational drug design for targeting AKT1. AbbreviationAKT1, AKT Serine/Threonine Kinase 1; ADME, absorption, distribution, metabolism, excretion; TOPKAT, toxicity prediction by Computer assisted technology; CCK8, Cell Counting Kit 8; ELISA, Enzyme-linked immunosorbent assay; CYP2D6, cytochrome P4502D6 inhibition; GBM, Glioblastoma; AGC kinase, protein kinase A, G, and C families (PKA, PKC, PKG); PKB, protein kinase B; PAM pathway, PI3K/AKT/mTOR pathway; OS, overall survival; PFS, progression-free survival; LD50, lethal dose half in rats; LOAEL, lowest observed adverse effect level; NPT, normal pressure and temperature; PME, particle mesh Ewald; LINCS, linear constraint solver; RMSD, root-mean-square deviation; BBB, blood–brain barrier; DS, Discovery Studio; DTP, Developmental toxicity potential; PPB, Plasma protein binding; MTD, Maximum Tolerated Dosage; AB, Aerobic Biodegradability; NTP, US. National Toxicology Program; DTP, developmental toxicity potential.
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spelling pubmed-92759692022-07-13 Identification of novel natural inhibitors targeting AKT Serine/Threonine Kinase 1 (AKT1) by computational study Zhong, Sheng Hou, Yuanyuan Zhang, Zhiyun Guo, Zhen Yang, Wenzhuo Dou, Gaojing Lv, Xiaye Wang, Xinhui Ge, Junliang Wu, Bo Pan, Xuefeng Wang, Hongyu Yang, Qunying Mou, Yonggao Bioengineered Research Paper Despite great progress, the current cancer treatments often have obvious toxicity and side effects. and a poor prognosis (some patients). One of the reasons for the poor prognosis is that certain enzymes prevent anticancer drugs from killing tumor cells. AKT1 is involved in regulating PI3K/AKT/mTOR, a tumor-generating pathway. Ipatasertib, a highly selective inhibitor of AKT1, is widely used in the treatment of tumors. In this study, many structural and biochemical methodswere used to find better AKT1(Threonine Kinase 1) inhibitors, which laid a foundation for the further development of AKT1 inhibitors and provided new drugs for the treatment of tumors. ZINC15 database and Discovery Studio 4.5, a computer-aided drug screening software with many modules (LibDock for virtual screening, ADME (Absorption, Distribution, Metabolism, Excretion) and TOPKAT (toxicity prediction module) for the toxicity and properties analysis, and MD simulation for stability prediction), were employed. CCK8 assay, ELISA assay genicity and higher tolerance to cytochrome P4502D6. MD simulations indicated they could bind with AKT1 stably in the natural environment. The cell experiment and specific assay for AKT1 inhibition showed they could inhibit the proliferation and AKT1 expression of MG63 cells (Osteosarcoma cells). Moreover, these novel compounds with structural modifications can be potential contributors that lead to further rational drug design for targeting AKT1. AbbreviationAKT1, AKT Serine/Threonine Kinase 1; ADME, absorption, distribution, metabolism, excretion; TOPKAT, toxicity prediction by Computer assisted technology; CCK8, Cell Counting Kit 8; ELISA, Enzyme-linked immunosorbent assay; CYP2D6, cytochrome P4502D6 inhibition; GBM, Glioblastoma; AGC kinase, protein kinase A, G, and C families (PKA, PKC, PKG); PKB, protein kinase B; PAM pathway, PI3K/AKT/mTOR pathway; OS, overall survival; PFS, progression-free survival; LD50, lethal dose half in rats; LOAEL, lowest observed adverse effect level; NPT, normal pressure and temperature; PME, particle mesh Ewald; LINCS, linear constraint solver; RMSD, root-mean-square deviation; BBB, blood–brain barrier; DS, Discovery Studio; DTP, Developmental toxicity potential; PPB, Plasma protein binding; MTD, Maximum Tolerated Dosage; AB, Aerobic Biodegradability; NTP, US. National Toxicology Program; DTP, developmental toxicity potential. Taylor & Francis 2022-05-21 /pmc/articles/PMC9275969/ /pubmed/35603567 http://dx.doi.org/10.1080/21655979.2021.2011631 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
Zhong, Sheng
Hou, Yuanyuan
Zhang, Zhiyun
Guo, Zhen
Yang, Wenzhuo
Dou, Gaojing
Lv, Xiaye
Wang, Xinhui
Ge, Junliang
Wu, Bo
Pan, Xuefeng
Wang, Hongyu
Yang, Qunying
Mou, Yonggao
Identification of novel natural inhibitors targeting AKT Serine/Threonine Kinase 1 (AKT1) by computational study
title Identification of novel natural inhibitors targeting AKT Serine/Threonine Kinase 1 (AKT1) by computational study
title_full Identification of novel natural inhibitors targeting AKT Serine/Threonine Kinase 1 (AKT1) by computational study
title_fullStr Identification of novel natural inhibitors targeting AKT Serine/Threonine Kinase 1 (AKT1) by computational study
title_full_unstemmed Identification of novel natural inhibitors targeting AKT Serine/Threonine Kinase 1 (AKT1) by computational study
title_short Identification of novel natural inhibitors targeting AKT Serine/Threonine Kinase 1 (AKT1) by computational study
title_sort identification of novel natural inhibitors targeting akt serine/threonine kinase 1 (akt1) by computational study
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9275969/
https://www.ncbi.nlm.nih.gov/pubmed/35603567
http://dx.doi.org/10.1080/21655979.2021.2011631
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