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Investigation of metabolite-protein interactions by transient absorption spectroscopy and in silico methods

AuthorsLimones-Herrero, D.; Palumbo, Fabrizio; Vendrell-Criado, V.; Andreu, Inmaculada; Lence, Emilio; González-Bello, Concepción; Miranda, M. A.; Jiménez, M.C.
Issue Date5-Feb-2020
PublisherElsevier BV
CitationSpectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy 226: 117652 (2020)
AbstractTransient absorption spectroscopy in combination with in silico methods has been employed to study the interactions between human serum albumin (HSA) and the anti-psychotic agent chlorpromazine (CPZ) as well as its two demethylated metabolites (MCPZ and DCPZ). Thus, solutions containing CPZ, MCPZ or DCPZ and HSA (molar ligand:protein ratios between 1:0 and 1:3) were submitted to laser flash photolysis and the ΔA value at λ = 470 nm, corresponding to the triplet excited state, was monitored. In all cases, the protein-bound ligand exhibited higher ΔAmax values measured after the laser pulse and were also considerably longer-lived than the non-complexed forms. This is in agreement with an enhanced hydrophilicity of the metabolites, due to the replacement of methyl groups with H that led to a lower extent of protein binding. For the three compounds, laser flash photolysis displacement experiments using warfarin or ibuprofen indicated Sudlow site I as the main binding site. Docking and molecular dynamics simulation studies revealed that the binding mode of the two demethylated ligands with HSA would be remarkable different from CPZ, specially for DCPZ, which appears to come from the different ability of their terminal ammonium groups to stablish hydrogen bonding interactions with the negatively charged residues within the protein pocket (Glu153, Glu292) as well as to allocate the methyl groups in an apolar environment. DCPZ would be rotated 180° in relation to CPZ locating the aromatic ring away from the Sudlow site I of HSA.
Publisher version (URL)http://dx.doi.org/10.1016/j.saa.2019.117652
Identifiersdoi: 10.1016/j.saa.2019.117652
issn: 1386-1425
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