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1.
Ensemble Docking Coupled to Linear Interaction Energy Calculations for Identification of Coronavirus Main Protease (3CLpro) Non-Covalent Small-Molecule Inhibitors
Marko Jukič, Dušanka Janežič, Urban Bren, 2020, original scientific article

Abstract: SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new strain of Coronaviridae. In the closing 2019 to early 2020 months, the virus caused a global pandemic of COVID-19 disease. We performed a virtual screening study in order to identify potential inhibitors of the SARS-CoV-2 main viral protease (3CLpro or Mpro). For this purpose, we developed a novel approach using ensemble docking high-throughput virtual screening directly coupled with subsequent Linear Interaction Energy (LIE) calculations to maximize the conformational space sampling and to assess the binding affinity of identified inhibitors. A large database of small commercial compounds was prepared, and top-scoring hits were identified with two compounds singled out, namely 1-[(R)-2-(1,3-benzimidazol-2-yl)-1-pyrrolidinyl]-2-(4-methyl-1,4-diazepan-1-yl)-1-ethanone and [({(S)-1-[(1H-indol-2-yl)methyl]-3-pyrrolidinyl}methyl)amino](5-methyl-2H-pyrazol-3-yl)formaldehyde. Moreover, we obtained a favorable binding free energy of the identified compounds, and using contact analysis we confirmed their stable binding modes in the 3CLpro active site. These compounds will facilitate further 3CLpro inhibitor design.
Keywords: COVID-19, SARS-CoV-2, Mpro, 3CLpro, 3C-like protease, virtual screening, inhibitors, in silico drug design, free-energy calculations
Published: 10.12.2020; Views: 241; Downloads: 49
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2.
Scaffold hopping and bioisosteric replacements based on binding site alignments
Samo 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: 05.07.2017; Views: 591; Downloads: 286
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3.
Ligand-based virtual screening interface between PyMOL and LiSiCA
Athira 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: 27.06.2017; Views: 521; Downloads: 268
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4.
Role of magnesium ions in the reaction mechanism at the interface between Tm1631 protein and its DNA ligand
Mitja Ogrizek, Janez Konc, Urban Bren, Milan Hodošček, Dušanka Janežič, 2016, original scientific article

Abstract: A protein, Tm1631 from the hyperthermophilic organism Thermotoga maritima belongs to a domain of unknown function protein family. It was predicted that Tm1631 binds with the DNA and that the Tm1631–DNA complex is an endonuclease repair system with a DNA repair function (Konc et al. PLoS Comput Biol 9(11): e1003341, 2013). We observed that the severely bent, strained DNA binds to the protein for the entire 90 ns of classical molecular dynamics (MD) performed; we could observe no significant changes in the most distorted region of the DNA, where the cleavage of phosphodiester bond occurs. In this article, we modeled the reaction mechanism at the interface between Tm1631 and its proposed ligand, the DNA molecule, focusing on cleavage of the phosphodiester bond. After addition of two Mg2+ ions to the reaction center and extension of classical MD by 50 ns (totaling 140 ns), the DNA ligand stayed bolted to the protein. Results from density functional theory quantum mechanics/molecular mechanics (QM/MM) calculations suggest that the reaction is analogous to known endonuclease mechanisms: an enzyme reaction mechanism with two Mg2+ ions in the reaction center and a pentacovalent intermediate. The minimum energy pathway profile shows that the phosphodiester bond cleavage step of the reaction is kinetically controlled and not thermodynamically because of a lack of any energy barrier above the accuracy of the energy profile calculation. The role of ions is shown by comparing the results with the reaction mechanisms in the absence of the Mg2+ ions where there is a significantly higher reaction barrier than in the presence of the Mg2+ ions.
Keywords: methods of analysis, computer science, magnesium ions, preteins, DNA
Published: 26.06.2017; Views: 541; Downloads: 321
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