Decoding Surface Interaction of VIVO Metallodrug Candidates with Lysozyme
Sciortino, Giuseppe (Universitat Autònoma de Barcelona. Departament de Química)
Sanna, Daniele (Consiglio Nazionale delle Ricerche. Istituto di Chimica Biomolecolare)
Ugone, Valeria (Università di Sassari. Dipartimento di Chimica e Farmacia)
Lledós, Agustí (Universitat Autònoma de Barcelona. Departament de Química)
Maréchal, Jean-Didier (Universitat Autònoma de Barcelona. Departament de Química)
Garribba, Eugenio (Università di Sassari. Dipartimento di Chimica e Farmacia)

Data:	2018
Resum:	The interaction of metallodrugs with proteins influences their transport, uptake, and mechanism of action. In this study, we present an integrative approach based on spectroscopic (EPR) and computational (docking) tools to elucidate the noncovalent binding modes of various VIVO compounds with lysozyme, a prototypical model of protein receptor. Five VIVO-flavonoid drug candidates formed by quercetin (que), morin (mor), 7,8-dihydroxyflavone (7,8-dhf), chrysin (chr), and 5-hydroxyflavone (5-hf) - effective against several osteosarcoma cell lines - and two benchmark VIVO species of acetylacetone (acac) and catechol (cat) are evaluated. The results show a gradual variation of the EPR spectra at room temperature, which is associated with the strength of the interaction between the square pyramidal complexes [VOL2] and the surface residues of lysozyme. The qualitative strength of the interaction from EPR is [VO(que)2]2- ? [VO(mor)2] > [VO(7,8-dhf)2]2- > [VO(chr)2] ? [VO(5-hf)2] > [VO(acac)2] ? [VO(cat)2]2-. This observation is compared with protein-ligand docking calculations with GOLD software examining the GoldScore scoring function (F), for which hydrogen bond and van der Waals contact terms have been optimized to account for the surface interaction. The best predicted binding modes display an energy trend in good agreement with the EPR spectroscopy. Computation indicates that the strength of the interaction can be predicted by the Fmax value and depends on the number of OH or CO groups of the ligands that can interact with different sites on the protein surface and, more particularly, with those in the vicinity of the active site of the enzyme. The interaction strength determines the type of signal revealed (rigid limit, slow tumbling, or isotropic) in the EPR spectra. Spectroscopic and computational results also suggest that there are several sites with comparable binding energy, with the V complexes distributing among them in a bound state and in aqueous solution in an unbound state. This kind of study and analysis could be generalized to determine the noncovalent binding modes of a generic metal species with a generic protein.
Ajuts:	Agencia Estatal de Investigación CTQ2017-87889-P Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-989
Nota:	Altres ajuts: COST Action CM1306
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Llengua:	Anglès
Document:	Article ; recerca ; Versió acceptada per publicar
Publicat a:	Inorganic chemistry, Vol. 57, Issue 8 (April 2018) , p. 4456-4469, ISSN 1520-510X

DOI: 10.1021/acs.inorgchem.8b00134

Postprint 41 p, 2.0 MB

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