A1 Refereed original research article in a scientific journal
Detection of binding sites on SARS-CoV-2 Spike protein receptor-binding domain by molecular dynamics simulations in mixed solvents
Authors: Jokinen Elmeri M., Gopinath Krishnasamy, Kurkinen Sami T., Pentikäinen Olli T.
Publisher: Institute of Electrical and Electronics Engineers
Publication year: 2021
Journal: IEEE/ACM Transactions on Computational Biology and Bioinformatics
Journal name in source: IEEE/ACM transactions on computational biology and bioinformatics
Journal acronym: IEEE/ACM Trans Comput Biol Bioinform
Volume: 18
Issue: 4
First page : 1281
Last page: 1289
ISSN: 1545-5963
eISSN: 1557-9964
DOI: https://doi.org/10.1109/TCBB.2021.3076259
Abstract
The novel SARS-CoV-2 uses the ACE2 (Angiotensin-Converting Enzyme 2) receptor as an entry point. Insights on S protein receptor-binding domain (RBD) interaction with ACE2 receptor and drug repurposing has accelerated drug discovery for the novel SARS-CoV-2 infection. Finding small molecule binding sites in the S protein and ACE2 interface is crucial in the search of effective drugs to prevent viral entry. In this study, we employed molecular dynamics simulations in mixed solvents together with virtual screening to identify small molecules that could be potential inhibitors of S protein ACE2 interaction. Observation of organic probe molecule localization during the simulations revealed multiple sites at the S protein surface related to a small molecule, antibody, and ACE2 binding. In addition, a novel conformation of the S protein was discovered that could be stabilized by small molecules to inhibit attachment to ACE2. The most promising binding site on the RBD-ACE2 interface was targeted with virtual screening and top-ranked compounds (DB08248, DB02651, DB03714, and DB14826) are suggested for experimental testing. The protocol described here offers an extremely fast method for characterizing key proteins of a novel pathogen and for the identification of compounds that could inhibit or accelerate the spreading of the disease.
The novel SARS-CoV-2 uses the ACE2 (Angiotensin-Converting Enzyme 2) receptor as an entry point. Insights on S protein receptor-binding domain (RBD) interaction with ACE2 receptor and drug repurposing has accelerated drug discovery for the novel SARS-CoV-2 infection. Finding small molecule binding sites in the S protein and ACE2 interface is crucial in the search of effective drugs to prevent viral entry. In this study, we employed molecular dynamics simulations in mixed solvents together with virtual screening to identify small molecules that could be potential inhibitors of S protein ACE2 interaction. Observation of organic probe molecule localization during the simulations revealed multiple sites at the S protein surface related to a small molecule, antibody, and ACE2 binding. In addition, a novel conformation of the S protein was discovered that could be stabilized by small molecules to inhibit attachment to ACE2. The most promising binding site on the RBD-ACE2 interface was targeted with virtual screening and top-ranked compounds (DB08248, DB02651, DB03714, and DB14826) are suggested for experimental testing. The protocol described here offers an extremely fast method for characterizing key proteins of a novel pathogen and for the identification of compounds that could inhibit or accelerate the spreading of the disease.
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