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The effect of the Ala16Val mutation on the secondary structure of the manganese superoxide dismutase mitochondrial targeting sequence
Matic Broz, Veronika Furlan, Samo Lešnik, Marko Jukič, Urban Bren, 2022, izvirni znanstveni članek

Opis: 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.
Ključne besede: manganese superoxide dismutase, polymorphism rs4880, mutation Ala16Val, molecular dynamics simulations, oxidative stress
Objavljeno v DKUM: 21.08.2023; Ogledov: 315; Prenosov: 10
.pdf Celotno besedilo (5,14 MB)
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Scaffold hopping and bioisosteric replacements based on binding site alignments
Samo Lešnik, Janez Konc, Dušanka Janežič, 2016, izvirni znanstveni članek

Opis: 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.
Ključne besede: bioisosteres, scaffold hopping, protein alignment, ProBiS, drug design, analysis methods, matter structure, modelling
Objavljeno v DKUM: 05.07.2017; Ogledov: 1184; Prenosov: 417
.pdf Celotno besedilo (2,30 MB)
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Ligand-based virtual screening interface between PyMOL and LiSiCA
Athira Dilip, Samo Lešnik, Tanja Štular, Dušanka Janežič, Janez Konc, 2016, izvirni znanstveni članek

Opis: 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.
Ključne besede: LiSiCa, PyMOL, informatics, applications
Objavljeno v DKUM: 27.06.2017; Ogledov: 1174; Prenosov: 341
.pdf Celotno besedilo (1,26 MB)
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