1,721,082 research outputs found
Reactivity of N-Heterocyclic Carbene Half-Sandwich Ru-, Os-, Rh-, and Ir-Based Complexes with Cysteine and Selenocysteine: A Computational Study
No full textThe structure and the reactivity of four half-sandwich metal complexes of Ru-II, Os-II, Rh-III, and Ir-III were investigated by means of density functional theory approaches. These piano-stool complexes, grouped in cym-bound complexes, Ru-II(cym)(dmb)Cl-2, 1, and Os-II(cym)(dmb)Cl-2, 2, and Cp*-bound complexes, Rh-III(Cp*)(dmb)Cl-2, 3, and Ir-III(Cp*)(dmb)-Cl-2, 4, with cym = eta(6)-p-cymene, Cp* = eta(5)-pentamethylcyclopentadienyl, and dmb = 1,3-dimethylbenzimidazol-2-ylidene, were recently proposed as anticancer metallodrugs that preferably target Cys- or Sec-containing proteins. Thus, density functional theory calculations were performed here to characterize in detail the thermodynamics and the kinetics underlining the targeting of these metallodrugs at either neutral or anionic Cys and Sec side chains. Calculations evidenced that all these complexes preferably target at Cys or Sec via chloro exchange, although cym-bound and Cp*-bound complexes resulted to be more prone to bind at neutral or anionic forms, respectively, of these soft protein sites. Further decomposition analyses of the activation free energies for the reaction between 1-4 complexes and either Cys or Sec, paralleled with the comparison among the optimized transition-state structures, allowed us to spotlight the significant role played by solvation in determining the overall reactivity and selectivity expected for these prototypical metallodrugs
Combined computational and bioinformatic approach to uncover the pre-covalent protein interactions of auranofin and its chlorido derivative Au(PEt3)Cl
No full textSelenocysteine of thioredoxin reductase as the primary target for the antitumor metallodrugs: A computational point of view
No full textSelenocysteine (Sec) has been recognized as a soft metal-coordinating residue that dues its relevance to the important role played in the catalytic activity of thioredoxin reductase (TrxR), a well-characterized an-ticancer target. Thus, several computational studies have been devoted to the metalation of this Se-based residue and several metal scaffolds have been proposed as potential Sec-binders, i.e. TrxR inhibitors. Here, we reported an overview of the chemical features of Sec, as well as of typical Sec-binding metal com-plexes, and of the computational studies carried on metallodrugs that primary target TrxR, by specifically posing our attention to antitumour metallodrugs based on Au(I), Au(III), Ag(I), Pt(II), Pt(IV), Ru(II), Ru(III), and Rh(III) metal centers. Moreover, we provided a computational insight on the available structural data and highlighted how an optimal articulation of computational methods and modeling of the metallodrug-target system may expand our understanding of the targeting of TrxR active site by metallic scaffolds.(c) 2022 Elsevier B.V. All rights reserved
Computational Studies Unveiling the Mechanism of Action of Selected Pt-, Te-, Au-, Rh-, Ru-Based Drugs
No full textModern medicinal chemistry is unimaginable without the employment of metallodrugs, which form a crucial source of novel anticancer, antiviral, antibacterial, and antiparasitic agents. The wide variety of molecular geometries, availability of several oxidation states, redox properties are ascribable to the presence of a metal center that can be exploited in the design of bioactive metal scaffolds with various modes of action, different selectivities, and activation mechanisms. This minireview focuses on an abridged account of the computational studies of the mechanism of action of selected Pt-, Te-, Au-, Rh-, Ru-based drugs, carried out in our group. This account is specifically focused on how the molecular geometry and the reactivity with the biological milieu may influence the modus operandi of these metal scaffolds
Dual Biomolecule Recognition by Diruthenium Paddlewheel Complexes: A Combined Computational Thermodynamics and Bioinformatic Structural Analysis
No full text: The development of novel metallodrugs is an important direction to address the limitations of conventional therapeutics. In this study, we investigated the dual biomolecule recognition capabilities of diruthenium paddlewheel complexes, a promising class of anticancer agents. We integrated two complementary approaches: density functional theory (DFT) calculations and bioinformatic structural analysis. Our DFT calculations characterized the thermodynamic feasibility of axial ligand substitution by key protein nucleophiles, namely cysteine (Cys), histidine (His), and adenine, while also probing the resulting structural motifs, including the effect on the ruthenium-ruthenium (Ru─Ru) bond distance. This analysis revealed the energetic spontaneity of complex formation with these nucleophiles and, notably, a nuanced flexibility of the Ru─Ru core that accommodates diverse ligand combinations. Subsequently, the computationally derived geometric assets were utilized to perform a comprehensive motif search within the Protein Data Bank (PDB) database. The PDB screening successfully identified the presence of these motifs, particularly Cys-His, Cys-Cys, and His-His, within numerous protein structures, including several clinically relevant targets. This work confirms the potential of the diruthenium paddlewheel complex as a multitargeting agent and establishes a robust, integrated methodology for the rational design and prevalidation of such metallodrugs by bridging atomic-level theoretical understanding with real-world biological structural data
A computational insight on the aromatic amino acids conjugation with [Cp*Rh(H2O)3]2+ by using the meta-dynamics/FMO3 approach
No full textContext: Rh(III) complexes demonstrated to exert promising pharmacological effects with potential applications as anti-cancer, anti-bacterial, and antimicrobial agents. One important Rh(III)-ligand is the pentamethylcyclopentadienyl (Cp*) group forming in water the [Cp*Rh(H2O)3]2+ complex. Among of its attractive chemical properties is the ability to react specifically with Tyr amino acid side chain of G-protein-coupled receptor (GPCR) peptides by means of highly chemoselective bioconjugation reaction, at room temperature and at pH 5-6. In this computational work, in order to deepen the mechanism of this chemoselective conjugation, we study the ligand exchange reaction between [Cp*Rh(H2O)3]2+ and three small molecules, namely p-cresol, 3-methylimidazole, and toluene, selected as mimetic of aromatic side chains of tyrosine (Tyr), tryptophan (Trp) and phenylalanine (Phe), respectively. Our outcomes suggest that the high selectivity for Tyr side chain might be related to OH group able to affect both thermodynamic and kinetic of ligand exchange reaction, due to its ability to act as both H bond acceptor and donor. These mechanistic aspects can be used to design new metal drugs containing the [Cp*Rh]2+ scaffold targeting specifically Tyr residues involved in biological/pathological processes such as phosphorylation by means of Tyr-kinase enzyme and protein-protein interactions. Methods: The geometry of three encounter complexes and product adducts were optimized at the B3LYP//CPCM/ωB97X-D level of theory, adopting the 6-311+G(d,p) basis set for all non-metal atoms and the LANL2DZ pseudopotential for the Rh atom. Meta-dynamics RMSD (MTD(RMSD)) calculations at GFN2-xTB level of theory were performed in NVT conditions at 298.15 K to investigate the bioconjugation reactions (simulation time: 100 ps; integration step 2.0; implicit solvent model: GBSA). The MTD(RMSD) simulation was performed in two replicates for each encounter complex. Final representative subsets of 100 structures for each run were gained with a sampling rate of 1 ps and analyzed by performing single point calculations using the FMO3 method at RI-MP2/6-311G//PCM[1] level of theory, adopting the MCP-TZP core potential for Rh atom
Molecular dynamics simulation of the Pb(II) coordination in biological media via cationic dummy atom models
Full text linkThe coordination of Pb(II) in aqueous solutions containing thiols is a pivotal topic to the understanding of the pollutant potential of this cation. Based on its hard/soft borderline nature, Pb(II) forms stable hydrated ions as well as stable complexes with the thiol groups of proteins. In this paper, the modeling of Pb(II) coordination via classical molecular dynamics simulations was investigated to assess the possible use of non-bonded potentials for the description of the metal-ligand interaction. In particular, this study aimed at testing the capability of cationic dummy atom schemes-in which part of the mass and charge of the Pb(II) is fractioned in three or four sites anchored to the metal center-in reproducing the correct coordination geometry and, also, in describing the hard/soft borderline character of this cation. Preliminary DFT calculations were used to design two topological schemes, PB3 and PB4, that were subsequently implemented in the Amber force field and employed in molecular dynamics simulation of either pure water or thiol/thiolate-containing aqueous solutions. The PB3 scheme was then tested to model the binding of Pb(II) to the lead-sensing protein pbrR. The potential use of CDA topological schemes in the modeling of Pb(II) coordination was here critically discussed
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