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2. Molekulska dinamika vezave cianidina na SIRT6: pomembnost za človeško zdravje : diplomsko delo univerzitetnega študijskega programa I. stopnjeGašper Dimnik, 2025, undergraduate thesis Abstract: Z namenom, ne le podaljšati življensko dobo, temveč tudi ohraniti daljše obdobje zdravja človeka, je vedno več raziskav usmerjenih v razvoj naravnih modulatorjev encimske aktivnosti človeškega sirtuina 6 (SIRT6). Ta namreč sodeluje pri več celičnih procesih, povezanih s staranjem, ki bi jih lahko regulirali s pomočjo naravnih modulatorjev, flavonoidov. Med slednje spadata cianidin ter njegov glukozid cianidin-3-O-glukozid (Cy3G). S pomočjo računalniških orodij smo simulirali molekulske dinamike (MD) vezave teh ligandov na kompleks SIRT6 in adenozin difosfat(ADP)-riboze. Z analizo vrednosti RMSD ter časovnega deleža vodikovih vezi simulacije MD smo preučili stabilnost obeh ligandov v kompleksih ter določili stabilnejšega izmed obeh. Izkazalo se je, da se oba liganda stabilizirata v proteinskih kompleksih po 50 ns simulacije MD, a je ta stabilizacija pri cianidinu močnejša. Analiza vrednosti RMSD za izključno liganda je prav tako pokazala, da je cianidin stabilnejši izmed obeh. Dokončno potrditev tega smo dokazali z analizo vodikovih vezi med ligandoma ter SIRT6. Ugotovili smo, da se pri Cy3G karakteristične vodikove vezi vzpostavijo po 20 ns simulacije MD oziroma po zvišanju vrednosti RMSD. To poveča razliko med eksperimentalno določeno prvotno strukturo ter končno strukturo proteinskega kompleksa SIRT6–Cy3G. To dokazuje, da je cianidin boljša izbira za razvoj selektivnih in učinkovitih modulatorjev SIRT6, a je zaradi razlik v farmakokinetiki smotrno preučiti oba liganda. Te ugotovitve bi lahko vodile v raziskovanje in razvoj terapevtskih učinkovin za zdravljenje bolezni staranja, kot je na primer rak.
Keywords: bolezni staranja, SIRT6, molekulska dinamika, naravni modulatorji encimov, cianidin, cianidin-3-O-glukozid
Published in DKUM: 18.09.2025; Views: 0; Downloads: 8
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3. Unveiling polyphenol-protein interactions : a comprehensive computational analysisSamo Lešnik, Marko Jukič, Urban Bren, 2025, original scientific article Abstract: Our study investigates polyphenol-protein interactions, analyzing their structural diversity and dynamic behavior. Analysis of the entire Protein Data Bank reveals diverse polyphenolic structures, engaging in various noncovalent interactions with proteins. Interactions observed across crystal structures among diverse polyphenolic classes reveal similarities, underscoring consistent patterns across a spectrum of structural motifs. On the other hand, molecular dynamics (MD) simulations of polyphenol-protein complexes unveil dynamic binding patterns, highlighting the influx of water molecules into the binding site and underscoring limitations of static crystal structures. Water-mediated interactions emerge as crucial in polyphenol-protein binding, leading to variable binding patterns observed in MD simulations. Comparison of high- and low-resolution crystal structures as starting points for MD simulations demonstrates their robustness, exhibiting consistent dynamics regardless of the quality of the initial structural data. Additionally, the impact of glycosylation on polyphenol binding is explored, revealing its role in modulating interactions with proteins. In contrast to synthetic drugs, polyphenol binding seems to exhibit heightened flexibility, driven by dynamic water-mediated interactions, which may also facilitate their promiscuous binding. Comprehensive dynamic studies are, therefore essential to understand polyphenol-protein recognition mechanisms. Overall, our study provides novel insights into polyphenol-protein interactions, informing future research for harnessing polyphenolic therapeutic potential through rational drug design.
Keywords: polyphenols, polyphenol-protein complexes, molecular dynamics simulations, noncovalent interactions, water-mediated interactions, glycosylation, dynamic behavior
Published in DKUM: 14.08.2025; Views: 0; Downloads: 3
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4. 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: 7
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5. Computational analysis of S1PR1 SNPs reveals drug binding modes relevant to multiple sclerosis treatmentKatarina Kores, Samo Lešnik, Urban Bren, 2024, original scientific article Keywords: molecular dynamics simulations, personalized therapy, single nucleotide polymorphisms, SNPs, linear interaction energy, LIE, multiple sclerosis, MS
Published in DKUM: 03.02.2025; Views: 0; Downloads: 4
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6. Mehanizem stabilizacije humanega transportnega proteina transtiretina z rožmarinsko kislinoMeta Kočevar, 2020 Abstract: Dedna transtiretinska amiloidoza je avtosomno dominantna bolezen. Nastane kot posledica mutacije v proteinu transtiretinu. Mutacije povzročajo strukturne spremembe proteina, ki jim sledi disociacija v monomere in kasneje agregacija monomerov ter tvorba amiloidnih vlakenc. Vlakenca se nalagajo v tkivih kot so živčevje, srce in ledvice. Nestabilno strukturo proteina, ki jo povzročajo mutacije, je možno stabilizirati z vezavo majhnih molekul na protein. Ena izmed takšnih molekul je rožmarinska kislina.
V magistrskem delu smo z uporabo računalniških simulacij molekulske dinamike ugotavljali, kako mutacija V30M vpliva na stabilnost strukture proteina transtiretina. Na protein smo vezali tudi rožmarinsko kislino in opazovali, ali se z vezavo stabilnost proteina spremeni. Pri tem smo uporabili dva različna načina parametrizacije polja sil za rožmarinsko kislino.
Za pripravo 6 simulacij molekulske dinamike smo uporabili program CHARMM-GUI, za samo izvedbo simulacij pa program NAMD. Rezultate smo vizualno pregledali in analizirali s programoma Chimera in Cytoscape. Analiza trajektorij molekulskih dinamik je obsegala izračun srednjega kvadrata odstopanja, analizo vodikovih vezi in analizo vseh nekovalentnih kontaktov.
Rezultati, ki smo jih pri tem dobili, kažejo, da mutacija V30M povzroči manj stabilno strukturo transtiretina. Avtomatsko parametrizirana rožmarinska kislina na stabilnost kompleksa protein-ligand za nemutirani protein ni imela velikega vpliva, medtem ko je ročno parametrizirana rožmarinska kislina zmanjšala število kontaktov med nemutiranim proteinom in ligandom. V primeru vezave ročno parametrizirane rožmarinske kisline pa smo zaznali veliko število kontaktov med proteinom in ligandom. Ob vezavi rožmarinske kisline na nemutirani protein smo zaznali manjšo stabilnost proteina. Vezava rožmarinske kisline na mutirani protein pa izboljša stabilnost proteina.
Keywords: transtiretin, transtiretinska amiloidoza, rožmarinska kislina, simulacije molekulske dinamike, polje sil, stabilnost proteina
Published in DKUM: 10.10.2024; Views: 0; Downloads: 81
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7. 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: 28
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8. The effect of the Ala16Val mutation on the secondary structure of the manganese superoxide dismutase mitochondrial targeting sequenceMatic Broz, Veronika Furlan, Samo Lešnik, Marko Jukič, Urban Bren, 2022, original scientific article Abstract: Manganese Superoxide Dismutase (MnSOD) represents a mitochondrial protein that scavenges reactive oxygen species (ROS) responsible for oxidative stress. A known single nucleotide polymorphism (SNP) rs4880 on the SOD2 gene, causing a mutation from alanine to valine (Ala16Val) in the primary structure of immature MnSOD, has been associated with several types of cancer and other autoimmune diseases. However, no conclusive correlation has been established yet. This study aims to determine the effect of the alanine to valine mutation on the secondary structure of the MnSOD mitochondrial targeting sequence (MTS). A model for each variant of the MTS was prepared and extensively simulated with molecular dynamics simulations using the CHARMM36m force field. The results indicate that the alanine variant of the MTS preserves a uniform α-helical secondary structure favorable for the protein transport into mitochondria, whereas the valine variant quickly breaks down its α-helix. Thus, the alanine MTS represents the more active MnSOD variant, the benefits of which have yet to be determined experimentally.
Keywords: manganese superoxide dismutase, polymorphism rs4880, mutation Ala16Val, molecular dynamics simulations, oxidative stress
Published in DKUM: 21.08.2023; Views: 370; Downloads: 18
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9. Scaffold hopping and bioisosteric replacements based on binding site alignmentsSamo Lešnik, Janez Konc, Dušanka Janežič, 2016, original scientific article Abstract: Bioisosteric replacements and scaffold hopping play an important role in modern drug discovery and design, as they enable the change of either a core scaffold or substitutes in a drug structure, thereby facilitating optimization of pharmacokinetic properties and patenting, while the drug retains its activity. A new knowledge-based method was developed to obtain bioisosteric or scaffold replacements based on the extensive data existing in the Protein Data Bank. The method uses all-against-all ProBiS-based protein superimposition to identify ligand fragments that overlap in similar binding sites and could therefore be considered as bioisosteric replacements. The method was demonstrated on a specific example of drug candidate – a nanomolar butyrylcholinesterase inhibitor, on which bioisosteric replacements of the three ring fragments were performed. The new molecule containing bioisosteric replacements was evaluated virtually using AutoDock Vina; a similar score for the original and the compound with replacements was obtained, suggesting that the newly designed bioisostere compound might retain the potency of the original inhibitor.
Keywords: bioisosteres, scaffold hopping, protein alignment, ProBiS, drug design, analysis methods, matter structure, modelling
Published in DKUM: 05.07.2017; Views: 1237; Downloads: 442
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10. Ligand-based virtual screening interface between PyMOL and LiSiCAAthira Dilip, Samo Lešnik, Tanja Štular, Dušanka Janežič, Janez Konc, 2016, original scientific article Abstract: Ligand-based virtual screening of large small-molecule databases is an important step in the early stages of drug development. It is based on the similarity principle and is used to reduce the chemical space of large databases to a manageable size where chosen ligands can be experimentally tested. Ligand-based virtual screening can also be used to identify bioactive molecules with different basic scaffolds compared to already known bioactive molecules, thus having the potential to increase the structural variability of compounds. Here, we present an interface between the popular molecular graphics system PyMOL and the ligand-based virtual screening software LiSiCA available at http://insilab.org/lisica-plugin and demonstrate how this interface can be used in the early stages of drug discovery process.
Keywords: LiSiCa, PyMOL, informatics, applications
Published in DKUM: 27.06.2017; Views: 1251; Downloads: 378
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