Author: Stefano Leoni

"Dynamical Docking" of Cyclic Dinuclear Au(I) Bis-N-heterocyclic Complexes Facilitates Their Binding to G-Quadruplexes.

2022

With the aim to improve the design of metal complexes as stabilizers of noncanonical DNA secondary structures, namely, G-quadruplexes (G4s), a series of cyclic dinuclear Au(I) N-heterocyclic carbene complexes based on xanthine and benzimidazole ligands has been synthesized and characterized by various methods, including X-ray diffraction. Fluorescence resonance energy transfer (FRET) and CD DNA melting assays unraveled the compounds’ stabilization properties toward G4s of different topologies of physiological relevance. Initial structure–activity relationships have been identified and recognize the family of xanthine derivatives as those more selective toward G4s versus duplex DNA. The bind…

Inorganic ChemistryG-quadruplexPhysical and Theoretical ChemistryInorganic chemistry

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The mechanism of aquaporin inhibition by gold compounds elucidated by biophysical and computational methods

2017

The inhibition of water and glycerol permeation via human aquaglyceroporin-3 (AQP3) by gold(iii) complexes has been studied by stopped-flow spectroscopy and, for the first time, its mechanism has been described using molecular dynamics (MD), combined with density functional theory (DFT) and electrochemical studies. The obtained MD results showed that the most effective gold-based inhibitor, anchored to Cys40 in AQP3, is able to induce shrinkage of pores preventing glycerol and water permeation. Moreover, the good correlation between the affinity of the Au(iii) complex to Cys binding and AQP3 inhibition effects was highlighted, while no influence of the different oxidative character of the c…

Surfaces Coatings and FilmAquaporinCeramics and CompositeOxidative phosphorylationMolecular Dynamics Simulation010402 general chemistryElectrochemistry01 natural sciencesCatalysisCatalysiMolecular dynamicschemistry.chemical_compoundGold CompoundsJournal ArticleMaterials ChemistryGlycerolHumansOrganic chemistryAquaporin 3Molecular Structure010405 organic chemistryChemistryElectronic Optical and Magnetic MaterialChemistry (all)Metals and AlloysGeneral ChemistryPermeation0104 chemical sciencesSurfaces Coatings and FilmsElectronic Optical and Magnetic MaterialsSettore CHIM/03 - Chimica Generale E InorganicaCeramics and CompositesBiophysicsQuantum TheoryDensity functional theoryOrganogold CompoundsChemical Communications

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On the Mechanism of Gold/NHC Compounds Binding to DNA G-Quadruplexes: Combined Metadynamics and Biophysical Methods

2018

The binding modes and free-energy landscape of two AuI /N-heterocyclic carbene complexes interacting with G-quadruplexes, namely a human telomeric (hTelo) and a promoter sequence (C-KIT1), are studied here for the first time by metadynamics. The theoretical results are validated by FRET DNA melting assays and provide an accurate estimate of the absolute gold complex/DNA binding free energy. This advanced in silico approach is valuable to achieve rational drug design of selective G4 binders.

Molecular Structure010405 organic chemistryIn silicoMetadynamicsDrug designSequence (biology)General MedicineDNAGeneral Chemistryanticancer010402 general chemistryG-quadruplex01 natural sciencesCombinatorial chemistryCatalysis0104 chemical sciencesG-Quadruplexeschemistry.chemical_compoundNucleic acid thermodynamicsFörster resonance energy transferchemistryFluorescence Resonance Energy TransferN-heterocyclic carbenesGoldDNAAngewandte Chemie International Edition

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Mechanisms of irreversible aquaporin-10 inhibition by organogold compounds studied by combined biophysical methods and atomistic simulations

2021

Abstract The inhibition of glycerol permeation via human aquaporin-10 (hAQP10) by organometallic gold complexes has been studied by stopped-flow fluorescence spectroscopy, and its mechanism has been described using molecular modelling and atomistic simulations. The most effective hAQP10 inhibitors are cyclometalated Au(III) C^N compounds known to efficiently react with cysteine residues leading to the formation of irreversible C–S bonds. Functional assays also demonstrate the irreversibility of the binding to hAQP10 by the organometallic complexes. The obtained computational results by metadynamics show that the local arylation of Cys209 in hAQP10 by one of the gold inhibitors is mapped int…

waterBiophysicsGlycerol transportirreversible inhibitorsMolecular Dynamics SimulationAquaporinsBiochemistryBiophysical PhenomenaFluorescence spectroscopymetadynamicsBiomaterialsMolecular dynamicsGold CompoundsComputational chemistrygold compoundsHumansOrganogold CompoundsChemistryglycerol transportMetals and AlloysMetadynamicsPermeationSmall moleculeSpectrometry FluorescenceChemistry (miscellaneous)aquaglyceroporinOrganogold Compounds

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