1. Novel small-molecule inhibitors of the SARS-CoV-2 spike protein binding to neuropilin 1Anja Kolarič, Marko Jukič, Urban Bren, 2022, original scientific article Abstract: Furin cleavage of the SARS-CoV-2 spike protein results in a polybasic terminal sequence
termed the C-end rule (CendR), which is responsible for the binding to neuropilin 1 (NRP1), enhancing
viral infectivity and entry into the cell. Here we report the identification of 20 small-molecule
inhibitors that emerged from a virtual screening of nearly 950,000 drug-like compounds that bind
with high probability to the CendR-binding pocket of NRP1. In a spike NRP1 binding assay, two of
these compounds displayed a stronger inhibition of spike protein binding to NRP1 than the known
NRP1 antagonist EG00229, for which the inhibition of the CendR peptide binding to NRP1 was
also experimentally confirmed. These compounds present a good starting point for the design of
small-molecule antagonists against the SARS-CoV-2 viral entry.
Keywords: neuropilin 1, SARS-CoV-2, COVID-19, spike binding inhibitors, virtual screening, small-molecule antagonists, molecular docking, in vitro binding assay
Published in DKUM: 09.05.2025; Views: 0; Downloads: 0
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2. Inverse molecular docking elucidating the anticarcinogenic potential of the hop natural product xanthohumol and its metabolitesKatarina Kores, Zala Kolenc, Veronika Furlan, Urban Bren, 2022, original scientific article Abstract: Natural products from plants exert a promising potential to act as antioxidants, antimicrobials, anti-inflammatory, and anticarcinogenic agents. Xanthohumol, a natural compound from hops, is indeed known for its anticarcinogenic properties. Xanthohumol is converted into three metabolites: isoxanthohumol (non-enzymatically) as well as 8- and 6-prenylnaringenin (enzymatically). An inverse molecular docking approach was applied to xanthohumol and its three metabolites to discern their potential protein targets. The aim of our study was to disclose the potential protein
targets of xanthohumol and its metabolites in order to expound on the potential anticarcinogenic
mechanisms of xanthohumol based on the found target proteins. The investigated compounds were
docked into the predicted binding sites of all human protein structures from the Protein Data Bank,
and the best docking poses were examined. Top scoring human protein targets with successfully
docked compounds were identified, and their experimental connection with the anticarcinogenic
function or cancer was investigated. The obtained results were carefully checked against the existing
experimental findings from the scientific literature as well as further validated using retrospective
metrics. More than half of the human protein targets of xanthohumol with the highest docking scores
have already been connected with the anticarcinogenic function, and four of them (including two
important representatives of the matrix metalloproteinase family, MMP-2 and MMP-9) also have a
known experimental correlation with xanthohumol. Another important protein target is acyl-protein
thioesterase 2, to which xanthohumol, isoxanthohumol, and 6-prenylnaringenin were successfully
docked with the lowest docking scores. Moreover, the results for the metabolites show that their
most promising protein targets are connected with the anticarcinogenic function as well. We firmly
believe that our study can help to elucidate the anticarcinogenic mechanisms of xanthohumol and its
metabolites as after consumption, all four compounds can be simultaneously present in the organism.
Keywords: xanthohumol, metabolites, inverse molecular docking, anticarcinogenic effects
Published in DKUM: 10.04.2025; Views: 0; Downloads: 1
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3. Mechanistic insights into biological activities of polyphenolic compounds from rosemary obtained by inverse molecular dockingSamo Lešnik, Urban Bren, 2022, original scientific article Abstract: Rosemary (Rosmarinus officinalis L.) represents a medicinal plant known for its various
health-promoting properties. Its extracts and essential oils exhibit antioxidative, anti-inflammatory,
anticarcinogenic, and antimicrobial activities. The main compounds responsible for these effects are
the diterpenes carnosic acid, carnosol, and rosmanol, as well as the phenolic acid ester rosmarinic
acid. However, surprisingly little is known about the molecular mechanisms responsible for the
pharmacological activities of rosemary and its compounds. To discern these mechanisms, we performed a large-scale inverse molecular docking study to identify their potential protein targets. Listed
compounds were separately docked into predicted binding sites of all non-redundant holo proteins
from the Protein Data Bank and those with the top scores were further examined. We focused on
proteins directly related to human health, including human and mammalian proteins as well as
proteins from pathogenic bacteria, viruses, and parasites. The observed interactions of rosemary
compounds indeed confirm the beforementioned activities, whereas we also identified their potential
for anticoagulant and antiparasitic actions. The obtained results were carefully checked against the
existing experimental findings from the scientific literature as well as further validated using both
redocking procedures and retrospective metrics.
Keywords: rosemary, inverse molecular docking, carnosol, carnosic acid, rosmanol, rosmarinic acid
Published in DKUM: 10.04.2025; Views: 0; Downloads: 2
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4. 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: 26
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5. Design of Tetra-Peptide Ligands of Antibody Fc Regions Using In Silico Combinatorial Library ScreeningMarko Jukič, Sebastjan Kralj, Anja Kolarič, Urban Bren, 2023, original scientific article Abstract: Abstract
Peptides, or short chains of amino-acid residues, are becoming increasingly important as active ingredients of drugs and as crucial probes and/or tools in medical, biotechnological, and pharmaceutical research. Situated at the interface between small molecules and larger macromolecular systems, they pose a difficult challenge for computational methods. We report an in silico peptide library generation and prioritization workflow using CmDock for identifying tetrapeptide ligands that bind to Fc regions of antibodies that is analogous to known in vitro recombinant peptide libraries’ display and expression systems. The results of our in silico study are in accordance with existing scientific literature on in vitro peptides that bind to antibody Fc regions. In addition, we postulate an evolving in silico library design workflow that will help circumvent the combinatorial problem of in vitro comprehensive peptide libraries by focusing on peptide subunits that exhibit favorable interaction profiles in initial in silico peptide generation and testing.
Keywords: peptide design, in silico combinatorial library, peptide combinatorial library, peptide library design, high-throughput virtual screening, peptide molecular docking, antibody purification, peptide drug design, recombinant peptide libraries
Published in DKUM: 01.12.2023; Views: 353; Downloads: 88
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