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Title:Ensemble Docking Coupled to Linear Interaction Energy Calculations for Identification of Coronavirus Main Protease (3CLpro) Non-Covalent Small-Molecule Inhibitors
Authors:Jukič, Marko, Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia (Author)
Janežič, Dušanka, Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, SI-6000 Koper, Slovenia (Author)
Bren, Urban, Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia (Author)
Files:.pdf RAZ_Jukic_Marko_0.pdf (2,99 MB)
MD5: E0048AC34361BBE3D18A6A95B40BB45D
 
Language:English
Work type:Unknown ()
Typology:1.01 - Original Scientific Article
Organization:FKKT - Faculty of Chemistry and Chemical Engineering
Abstract:SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new strain of Coronaviridae. In the closing 2019 to early 2020 months, the virus caused a global pandemic of COVID-19 disease. We performed a virtual screening study in order to identify potential inhibitors of the SARS-CoV-2 main viral protease (3CLpro or Mpro). For this purpose, we developed a novel approach using ensemble docking high-throughput virtual screening directly coupled with subsequent Linear Interaction Energy (LIE) calculations to maximize the conformational space sampling and to assess the binding affinity of identified inhibitors. A large database of small commercial compounds was prepared, and top-scoring hits were identified with two compounds singled out, namely 1-[(R)-2-(1,3-benzimidazol-2-yl)-1-pyrrolidinyl]-2-(4-methyl-1,4-diazepan-1-yl)-1-ethanone and [({(S)-1-[(1H-indol-2-yl)methyl]-3-pyrrolidinyl}methyl)amino](5-methyl-2H-pyrazol-3-yl)formaldehyde. Moreover, we obtained a favorable binding free energy of the identified compounds, and using contact analysis we confirmed their stable binding modes in the 3CLpro active site. These compounds will facilitate further 3CLpro inhibitor design.
Keywords:COVID-19, SARS-CoV-2, Mpro, 3CLpro, 3C-like protease, virtual screening, inhibitors, in silico drug design, free-energy calculations
Year of publishing:2020
Numbering:24, 25
UDC:578.834
ISSN on article:1420-3049
COBISS_ID:42014467 New window
DOI:10.3390/molecules25245808 New window
NUK URN:URN:SI:UM:DK:MPK4OGWH
Views:241
Downloads:49
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Categories:Misc.
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Record is a part of a journal

Title:Molecules
Publisher:MDPI
ISSN:1420-3049

Document is financed by a project

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Project no.:P2-0046
Name:Separacijski procesi in produktna tehnika

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Project no.:J1-1715
Name:Atlas proteinskih interakcij za napovedovanje genskih variacij povezanih z interakcijami z zdravili in razvojem bolezni

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Project no.:J1-9186
Name:Razvoj novih računskih orodij na PDB ravni za odkrivanje zdravil

Licences

License:CC BY 4.0, Creative Commons Attribution 4.0 International
Link:http://creativecommons.org/licenses/by/4.0/
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
Licensing start date:10.12.2020

Secondary language

Language:English
Keywords:izračunavanja, inhibitorji, pokazatelji, proteaze, koronavirusi


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