1. Insights into chemopreventive effects of rosmarinic acid against aflatoxin B1-induced genotoxic effectsVeronika Furlan, Matjaž Novak, Martina Štampar, Alja Štern, Bojana Žegura, Urban Bren, 2025, izvirni znanstveni članek Povzetek: In this study, the chemopreventive effects of rosmarinic acid (RA), a major phenolic acid of the plant Rosmarinus officinalis L., against the carcinogenic naturally occurring mycotoxin aflatoxin B1 (AFB1) were investigated using both in silico and in vitro approaches. The in silico investigation of the chemical reactions between rosmarinic acid and the carcinogenic metabolite of AFB1, aflatoxin B1 exo-8,9-epoxide (AFBO), was conducted by activation free energies calculations with DFT functionals M11-L and MN12-L, in conjunction with the 6-311++G(d,p) flexible basis set and implicit solvation model density (SMD), according to a newly developed quantum mechanics-based protocol for the evaluation of carcinogen scavenging activity (QM-CSA). Following the computational analyses, the chemoprotective effects of RA were further studied in vitro in human hepatocellular carcinoma HepG2 cells by analyzing its influence on AFB1-induced genotoxicity using a comet assay, γH2AX, and p-H3, while its impact on cell proliferation and cell cycle modulation was assessed using flow cytometry. Our computational results revealed that the activation free energy required for the reaction of RA with AFBO (14.86 kcal/mol) is significantly lower than the activation free energy for the competing reaction of AFBO with guanine (16.88 kcal/mol), which indicates that RA acts as an efficient natural scavenger of AFBO, potentially preventing AFB1-specific DNA adduct formation. The chemoprotective activity of RA was confirmed through in vitro experiments, which demonstrated a statistically significant (p < 0.05) reduction in AFB1-induced single- and double-strand breaks in HepG2 cells exposed to a mixture of AFB1 and RA at non-cytotoxic concentrations. In addition, RA reversed the AFB1-induced reduction in cell proliferation.
Ključne besede: rosmarinic acid, aflatoxin B1, chemopreventive effects, antigenotoxic effects, density functional theory, chemical carcinogen scavenger, toxicology
Objavljeno v DiRROS: 03.07.2025; Ogledov: 439; Prenosov: 357
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2. Identification of triazolopyrimidinyl scaffold SARS-CoV-2 papain-like protease (PLpro) inhibitorSebastjan Kralj, Marko Jukič, Miha Bahun, Luka Kranjc, Anja Kolarič, Milan Hodošček, Nataša Poklar Ulrih, Urban Bren, 2024, izvirni znanstveni članek Povzetek: 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 papain-like 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.
Ključne besede: drug design, protease inhibitor, SARS-CoV-2, papain-like protease, PLpro, antiviral design, in silico drug design, CADD, virtual screening, HTVS, structure-based design
Objavljeno v DiRROS: 07.08.2024; Ogledov: 863; Prenosov: 717
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