1. Identification of furin protease small-molecule inhibitor with a 1,3-thiazol-2-ylaminosulfonyl scaffoldAnja Kolarič, Vid Ravnik, Sara Štumpf Horvat, Marko Jukič, Urban Bren, 2025, original scientific article Keywords: computer-assisted drug design, CADD, computer-assisted drug design, furin inhibitors, protease inhibitors, antivirals, protease inhibitors, furin assay, antiviral drug design
Published in DKUM: 20.03.2025; Views: 0; Downloads: 1
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2. Mechanistic insights of polyphenolic compounds from rosemary bound to their protein targets obtained by molecular dynamics simulations and free-energy calculationsSamo Lešnik, Marko Jukič, Urban Bren, 2023, original scientific article Keywords: rosemary, carnosic acid, carnosol, rosmanol, rosmarinic acid, polyphenols, molecular docking, molecular dynamics simulations, linear interaction energy calculations, water-mediated hydrogen-bonds, HIV-1 protease, K-RAS protein, factor X
Published in DKUM: 22.04.2024; Views: 185; Downloads: 27
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3. Identification of triazolopyrimidinyl scaffold SARS-CoV-2 papain-like protease (PLpro) inhibitorSebastjan Kralj, Marko Jukič, Miha Bahun, Luka Krajnc, Anja Kolarič, Milan Hodošček, Nataša Poklar Ulrih, Urban Bren, 2024, original scientific article Abstract: The global impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
and its companion disease, COVID-19, has reminded us of the importance of basic coronaviral
research. In this study, a comprehensive approach using molecular docking, in vitro assays, and
molecular dynamics simulations was applied to identify potential inhibitors for SARS-CoV-2 papainlike protease (PLpro), a key and underexplored viral enzyme target. A focused protease inhibitor
library was initially created and molecular docking was performed using CmDock software (v0.2.0),
resulting in the selection of hit compounds for in vitro testing on the isolated enzyme. Among
them, compound 372 exhibited promising inhibitory properties against PLpro, with an IC50 value of
82 ± 34 µM. The compound also displayed a new triazolopyrimidinyl scaffold not yet represented
within protease inhibitors. Molecular dynamics simulations demonstrated the favorable binding
properties of compound 372. Structural analysis highlighted its key interactions with PLpro, and
we stress its potential for further optimization. Moreover, besides compound 372 as a candidate for
PLpro inhibitor development, this study elaborates on the PLpro binding site dynamics and provides
a valuable contribution for further efforts in pan-coronaviral PLpro inhibitor development.
Keywords: drug design, protease inhibitor, SARS-CoV-2, papain-like protease, PLpro, antiviral design, in silico drug design, CADD, virtual screening, HTVS, structure-based design
Published in DKUM: 26.01.2024; Views: 358; Downloads: 29
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4. Ensemble Docking Coupled to Linear Interaction Energy Calculations for Identification of Coronavirus Main Protease (3CLpro) Non-Covalent Small-Molecule InhibitorsMarko Jukič, Dušanka Janežič, Urban Bren, 2020, original scientific article 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
Published in DKUM: 10.12.2020; Views: 1252; Downloads: 190
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