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Computational Design of Miniproteins as SARS-CoV-2 Therapeutic Inhibitors.
Jawad, Bahaa; Adhikari, Puja; Cheng, Kun; Podgornik, Rudolf; Ching, Wai-Yim.
  • Jawad B; Department of Physics and Astronomy, University of Missouri-Kansas City, Kansas City, MO 64110, USA.
  • Adhikari P; Department of Applied Sciences, University of Technology, Baghdad 10066, Iraq.
  • Cheng K; Department of Physics and Astronomy, University of Missouri-Kansas City, Kansas City, MO 64110, USA.
  • Podgornik R; Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
  • Ching WY; Wenzhou Institute of the University of Chinese Academy of Sciences, Wenzhou 325000, China.
Int J Mol Sci ; 23(2)2022 Jan 13.
Article in English | MEDLINE | ID: covidwho-1625319
ABSTRACT
A rational therapeutic strategy is urgently needed for combating SARS-CoV-2 infection. Viral infection initiates when the SARS-CoV-2 receptor-binding domain (RBD) binds to the ACE2 receptor, and thus, inhibiting RBD is a promising therapeutic for blocking viral entry. In this study, the structure of lead antiviral candidate binder (LCB1), which has three alpha-helices (H1, H2, and H3), is used as a template to design and simulate several miniprotein RBD inhibitors. LCB1 undergoes two modifications structural modification by truncation of the H3 to reduce its size, followed by single and double amino acid substitutions to enhance its binding with RBD. We use molecular dynamics (MD) simulations supported by ab initio density functional theory (DFT) calculations. Complete binding profiles of all miniproteins with RBD have been determined. The MD investigations reveal that the H3 truncation results in a small inhibitor with a -1.5 kcal/mol tighter binding to RBD than original LCB1, while the best miniprotein with higher binding affinity involves D17R or E11V + D17R mutation. DFT calculations provide atomic-scale details on the role of hydrogen bonding and partial charge distribution in stabilizing the minibinderRBD complex. This study provides insights into general principles for designing potential therapeutics for SARS-CoV-2.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Small Molecule Libraries / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23020838

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Small Molecule Libraries / Spike Glycoprotein, Coronavirus / SARS-CoV-2 / COVID-19 Language: English Year: 2022 Document Type: Article Affiliation country: Ijms23020838