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《BioRxiv，3月8日，AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2》

  • 来源专题：COVID-19科研动态监测
  • 编译者： zhangmin
  • 发布时间：2020-03-09

  • AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2

    Bowen Tang, Fengming He, Dongpeng Liu, Meijuan Fang, Zhen Wu, Dong Xu

    doi: https://doi.org/10.1101/2020.03.03.972133

    Abstract

    The focused drug repurposing of known approved drugs (such as lopinavir/ritonavir) has been reported failed for curing SARS-CoV-2 infected patients. It is urgent to generate new chemical entities against this virus. As a key enzyme in the life-cycle of coronavirus, the 3C-like main protease (3CLpro or Mpro) is the most attractive for antiviral drug design. Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with the fragment-based drug design (ADQN-FBDD) for generating potential lead compounds targeting SARS-CoV-2 3CLpro.

    *注，本文为预印本论文手稿，是未经同行评审的初步报告，其观点仅供科研同行交流，并不是结论性内容，请使用者谨慎使用.

  • 原文来源：https://www.biorxiv.org/content/10.1101/2020.03.03.972133v1
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    • 编译者：xuwenwhlib
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  • 《Science，9月9日，De novo design of picomolar SARS-CoV-2 miniprotein inhibitors》
    • 来源专题：COVID-19科研动态监测
    • 编译者：zhangmin
    • 发布时间：2020-09-16
    • De novo design of picomolar SARS-CoV-2 miniprotein inhibitors View ORCID ProfileLongxing Cao1,2, Inna Goreshnik1,2, View ORCID ProfileBrian Coventry1,2,3, View ORCID ProfileJames Brett Case4, View ORCID ProfileLauren Miller1,2, Lisa Kozodoy1,2, Rita E. Chen4,5, View ORCID ProfileLauren Carter1,2, View ORCID ProfileAlexandra C. Walls1, Young-Jun Park1, View ORCID ProfileEva-Maria Strauch6, View ORCID ProfileLance Stewart1,2, View ORCID ProfileMichael S. Diamond4,7, View ORCID ProfileDavid Veesler1, View ORCID ProfileDavid Baker1,2,8,* See all authors and affiliations Science  09 Sep 2020: eabd9909 DOI: 10.1126/science.abd9909 Abstract Targeting the interaction between the SARS-CoV-2 Spike protein and the human ACE2 receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer generated scaffolds were either built around an ACE2 helix that interacts with the Spike receptor binding domain (RBD), or docked against the RBD to identify new binding modes, and their amino acid sequences designed to optimize target binding, folding and stability. Ten designs bound the RBD with affinities ranging from 100pM to 10nM, and blocked ARS-CoV-2 infection of Vero E6 cells with IC 50 values between 24 pM and 35 nM; The most potent, with new binding modes, are 56 and 64 residue proteins (IC 50 ~ 0.16 ng/ml). Cryo-electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.
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