Study of the interaction between two newly synthesized cyclometallated platinum (II) complexes and human serum albumin: Spectroscopic characterization and docking simulation Reza Yousefi a,n , Roghayeh Mohammadi a , Asghar Taheri-Kafrani b , Mohammad Bagher Shahsavani a , Marzieh Dadkhah Aseman c , S. Masoud Nabavizadeh c , Mehdi Rashidi c , Najmeh Poursasan d , Ali-Akbar Moosavi-Movahedi d a Protein Chemistry Laboratory (PCL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran b Department of Biotechnology, Faculty of Advanced Sciences and Technologies, University of Isfahan, Isfahan 81746-73441, Iran c Department of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran d Institute of Biochemistry and Biophysics (IBB), the University of Tehran, Tehran, Iran article info Article history: Received 8 April 2014 Received in revised form 19 September 2014 Accepted 22 October 2014 Available online 13 November 2014 Keywords: Human serum albumin Pt (II) complexes UV–vis spectroscopy Fluorescence spectroscopy Circular dichroism Molecular docking simulation abstract This study describes HSA binding properties of two cyclometalated platinum (II) complexes with non- leaving lipophilic ligands; deprotonated 2-phenylpyridine (ppy): C 1 and deprotonated benzo [h] quinolone (bhq): C 2 , using UV–vis, fluorescence and circular dichroism (CD) spectroscopy. The absorption spectra of HSA decreased in the presence of increasing concentration of these complexes, reflecting HSA structural alteration after drug's binding. Also the thermodynamic parameters (ΔG, ΔH and ΔS) that obtained from Trp fluorescence study revealed that the interaction between these complexes and HSA were spontaneous. In addition, C 1 with flexible chemical structure indicated significantly higher fluorescence quenching and binding affinity to HSA than C 2 which possesses a higher structural rigidity. The ANS fluorescence results also indicated that two Pt (II) complexes were competing for binding to the hydrophobic regions of HSA. Moreover, CD results demonstrated that C 2 complex induced alteration of HSA conformation to more significant extent compared to C 1 . The molecular docking results revealed the involvement of π–π stacking and hydrophobic interaction between these complexes and the protein. Overall, this study may highlight the significance of structural flexibility in designing of future anticancer Pt (II) complexes with improved binding affinity for HSA. & 2014 Elsevier B.V. All rights reserved. 1. Introduction Studies on the interaction between a drug and protein are very important in biological, biomedical and pharmaceutical sciences [1–3]. Among investigated proteins, human serum albumin (HSA) is the most abundant carrier protein on blood stream with high affinity for a wide variety of ligands such as metabolites and drugs [4,5]. The important physiological functions of this protein are the storage and transport of wide range of endogenous and exogenous compounds such as fatty acids, hormones, bilirubin, drugs, etc., as well as, the maintenance of osmotic pressure and pH of the blood plasma [5]. The crystallographic analysis of HSA revealed that this protein contains a single chain of 585 residues with a molecular mass of 66.438 kDa. It constitutes of three homologous alpha-helical domains I (1–195), II (196–383) and III (384–585), that are packed in two separate sub-domains A and B. Although, HSA contains a single Trp residue at position 214, it is abundant of the amino acid residues such as Cys, Leu, Glu, and Lys. As indicated in the previous studies, the principal region of ligand binding on serum albumin is located between sub-domains IIA and IIIA [6,7]. The HSA/metal binding occurs mainly near Trp residue in sub-domain IIA, which also has been identified as a primary binding site for many drugs [2]. Although DNA is known as the final molecular target of platinum based drugs, their anticancer activity is also resulting of many other events, including their interaction with plasma proteins [8]. The interaction between Pt compounds and serum albumin is important on the basis of both drug delivery and possible development of acquired resistance/side effect [9]. Therefore, the mechanism under- lying Pt complex–albumin interaction seems essential for extending the knowledge of their therapeutic efficacy at the molecular level. The type of ligand around the metal center can affect various properties of platinum based complexes, including their solubility, reactivity, electronic and steric properties, as well as, geometry of Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/jlumin Journal of Luminescence http://dx.doi.org/10.1016/j.jlumin.2014.10.055 0022-2313/& 2014 Elsevier B.V. All rights reserved. n Corresponding author. Tel.: þ98 7116137617, þ98 7116137665; fax: þ98 7112280916. E-mail address: ryousefi@shirazu.ac.ir (R. Yousefi). Journal of Luminescence 159 (2015) 139–146