1. Novel small-molecule inhibitors of the SARS-CoV-2 spike protein binding to neuropilin 1Anja Kolarič, Marko Jukič, Urban Bren, 2022, izvirni znanstveni članek Opis: 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.
Ključne besede: neuropilin 1, SARS-CoV-2, COVID-19, spike binding inhibitors, virtual screening, small-molecule antagonists, molecular docking, in vitro binding assay
Objavljeno v DKUM: 09.05.2025; Ogledov: 0; Prenosov: 1
 Celotno besedilo (6,27 MB)
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2. Commercial SARS-CoV-2 targeted, protease inhibitor focused and protein–protein interaction inhibitor focused molecular libraries for virtual screening and drug designSebastjan Kralj, Marko Jukič, Urban Bren, 2022, pregledni znanstveni članek Opis: Since December 2019, the new SARS-CoV-2-related COVID-19 disease has caused a global
pandemic and shut down the public life worldwide. Several proteins have emerged as potential
therapeutic targets for drug development, and we sought out to review the commercially available
and marketed SARS-CoV-2-targeted libraries ready for high-throughput virtual screening (HTVS).
We evaluated the SARS-CoV-2-targeted, protease-inhibitor-focused and protein–protein-interactioninhibitor-focused libraries to gain a better understanding of how these libraries were designed. The
most common were ligand- and structure-based approaches, along with various filtering steps, using
molecular descriptors. Often, these methods were combined to obtain the final library. We recognized
the abundance of targeted libraries offered and complimented by the inclusion of analytical data;
however, serious concerns had to be raised. Namely, vendors lack the information on the library
design and the references to the primary literature. Few references to active compounds were also
provided when using the ligand-based design and usually only protein classes or a general panel
of targets were listed, along with a general reference to the methods, such as molecular docking for
the structure-based design. No receptor data, docking protocols or even references to the applied
molecular docking software (or other HTVS software), and no pharmacophore or filter design
details were given. No detailed functional group or chemical space analyses were reported, and no
specific orientation of the libraries toward the design of covalent or noncovalent inhibitors could
be observed. All libraries contained pan-assay interference compounds (PAINS), rapid elimination
of swill compounds (REOS) and aggregators, as well as focused on the drug-like model, with the
majority of compounds possessing their molecular mass around 500 g/mol. These facts do not bode
well for the use of the reviewed libraries in drug design and lend themselves to commercial drug
companies to focus on and improve.
Ključne besede: targeted libraries, focused libraries, computer-aided drug design, virtual screening, in silico drug design, high-throughput virtual screening
Objavljeno v DKUM: 09.04.2025; Ogledov: 0; Prenosov: 3
Celotno besedilo (6,53 MB)
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3. 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, izvirni znanstveni članek Ključne besede: computer-assisted drug design, CADD, computer-assisted drug design, furin inhibitors, protease inhibitors, antivirals, protease inhibitors, furin assay, antiviral drug design
Objavljeno v DKUM: 20.03.2025; Ogledov: 0; Prenosov: 1
Celotno besedilo (6,26 MB) |
4. Študija in optimizacija vezave antikalinov na male molekule : diplomsko delo univerzitetnega študijskega programa I. stopnjeAlja Špec, 2024, diplomsko delo Opis: V diplomskem delu smo raziskovali optimizacijo vezave anitkalina na majhno molekulo s tehniko molekulskega sidranja in in silico mutageneze. Osredotočili smo se na razumevanje, kako lahko specifične mutacije aminokislin znotraj antikalina vplivajo na njegove interakcije z različnimi ligandi. Pri tem smo s programskim jezikom Python pripravili skripto, ki nam je pomagala pri izvedbi in silico mutageneze aminokislinskih ostankov in oceno vezave med proteinom in ligandom. Rezultati so pokazali potencialno ugodne mutacije, ki bi lahko povečale vezavno afiniteto liganda. Tako smo pokazali enostavni postopek, s katerim lahko optimiziramo vezavo testnih ligandov na antikaline in s tem skrajšamo in vitro postopke oz. efektivneje izvajamo laboratorijsko delo. Ugotovitve diplomske naloge pa prispevajo tudi dragocen vpogled v podrobnosti interakcij ligand-protein, saj lahko vezavno mesto antikalinov omogoči visoko selektivnost za vezavo preučevanih malih molekul.
Ključne besede: in silico mutageneza, antikalini, molekulsko sidranje, lipokalinske strukture, vezavno mesto
Objavljeno v DKUM: 15.07.2024; Ogledov: 132; Prenosov: 66
Celotno besedilo (1,95 MB) |
5. Primerjava proteomov glavnih predstavnikov virusov iz družine Filoviridae in identifikacija potencialnih vezavnih mest za načrtovanje ligandov : magistrsko deloKatja Gole, 2024, magistrsko delo Opis: Virus Ebola Zaire (EBOV) in virus Marburg Marburg (MARV) sta glavna predstavnika družine Filoviridae, ki pri ljudeh povzročata hudo virusno hemoragično mrzlico, s stopnjo smrtnosti do 90 %. Kljub temu je zaradi le občasnih izbruhov bolezni, ki jih ni možno predvideti, razvoj zdravil okrnjen in se izvaja predvsem v akademskih krogih. V magistrskem delu smo preverjali podobnost virusnih proteomov in vezavnih mest z namenom, da bi v prihodnje bilo možno načrtovati učinkovine, ki bi se lahko vezale na terapevtske tarče obeh virusov. EBOV in MARV kodirata enakih sedem proteinov, in sicer NP, VP35, VP40, GP, VP30, VP24 in L protein, ki imajo glede na informacije, ki smo jih pridobili s pomočjo podatkovnih zbirk UniProt in PDB, podobne funkcije in zgradbo. Podobnost proteomov smo potrdili še z BLAST analizo aminokislinskih sekvenc med posameznimi proteini obeh virusov, pri čemer se podobnost proteinov giblje med 44 in 55 %, oziroma 68 % v 1. delu sekvence L proteinov. S programom ProBiS smo glede na primerjavo z že znanimi strukturami podobnih proteinov določili potencialna vezavna mesta in pripadajoče potencialne ligande. Vezavna mesta smo opisali in jih primerjali s pomočjo superpozicije proteinov obeh virusov. Kot rezultat smo pridobili tri pare podobnih vezavnih mest, ki se kljub podobnosti razlikujejo v posameznih aminokislinah, kar smo dokazali z BLAST primerjavo. S PLIP analizo smo pokazali, da aminokislinski ostanki v vezavnem mestu posameznega virusa tvorijo podobne interakcije z enakimi ligandi in da s tem obstaja možnost načrtovanja terapevtikov, ki bi se hkrati vezali na tarče EBOV in MARV.
Ključne besede: Ebola, Marburg, BLAST, vezavna mesta, ProBiS, načrtovanje ligandov
Objavljeno v DKUM: 11.07.2024; Ogledov: 104; Prenosov: 32
Celotno besedilo (15,22 MB) |
6. Molecular Filters in Medicinal ChemistrySebastjan Kralj, Marko Jukič, Urban Bren, 2023, pregledni znanstveni članek Ključne besede: medicinal chemistry, filtering chemical libraries, chemical space, HTVS, virtual screening, computer aided drug-design, in silico drug design, bioinformatics, chemoinformatic, compound library
Objavljeno v DKUM: 20.05.2024; Ogledov: 168; Prenosov: 24
Celotno besedilo (1,66 MB)
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8. 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, izvirni znanstveni članek Ključne besede: 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
Objavljeno v DKUM: 22.04.2024; Ogledov: 185; Prenosov: 26
Celotno besedilo (2,99 MB)
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9. Conserved water networks identification for drug design using density clustering approaches on positional and orientational dataJelena Tošović, Domagoj Fijan, Marko Jukič, Urban Bren, 2022, izvirni znanstveni članek Ključne besede: cluster chemistry, hydrogen, ligands, molecules, oxygen
Objavljeno v DKUM: 10.04.2024; Ogledov: 221; Prenosov: 19
Celotno besedilo (9,65 MB)
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10. 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, izvirni znanstveni članek 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 DKUM: 26.01.2024; Ogledov: 358; Prenosov: 29
Celotno besedilo (6,86 MB) |
