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Characteristics of the Protoporphyrin IX Binding Sites on Human Serum Albumin Using Molecular Docking

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Characteristics of the Protoporphyrin IX Binding Sites on Human Serum Albumin Using Molecular Docking molecules Article Characteristics of the Protoporphyrin IX Binding Sites on Human Serum Albumin Using Molecular Docking Leszek Sułkowski 1,*, Bartosz Pawełczak 2, Mariola Chudzik 2 and Małgorzata Maci ˛azek-Jurczyk˙ 2 1 Department of General and Vascular Surgery, Regional Specialist Hospital, Bialska 104/118, 42-218 Cz˛estochowa,Poland 2 Department of Physical Pharmacy, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Jagiello´nska4, 41-200 Sosnowiec, Poland; [email protected] (B.P.); [email protected] (M.C.); [email protected] (M.M.-J.) * Correspondence: [email protected]; Tel.: +48-792-244-177 Academic Editors: Josef Jampilek and Atanas G. Atanasov Received: 25 September 2016; Accepted: 2 November 2016; Published: 17 November 2016 Abstract: Human serum albumin (HSA) is the main plasma protein responsible for a distribution of drugs in the human circulatory system. The binding to HSA is one of the factors that determines both the pharmacological actions and the side effects of drugs. The derivative of heme, protoporphyrin IX (PpIX), is a hydrophobic photosensitizer widely used in photodynamic diagnosis and therapy of various malignant disorders. Using absorption and fluorescence spectroscopy, it has been demonstrated that PpIX forms complexes with HSA. Its binding sites in the tertiary structure of HSA were found in the subdomains IB and IIA. PpIX binds to HSA in one class of binding sites with the association constant of 1.68 × 105 M−1 and 2.30 × 105 M−1 for an excitation at wavelength λex = 280 nm and 295 nm, respectively. The binding interactions between HSA and PpIX have been studied by means of molecular docking simulation using the CLC Drug Discovery Workbench (CLC DDWB) computer program. PpIX creates a strong ‘sandwich-type’ complex between its highly conjugated porphine system and aromatic side chains of tryptophan and tyrosine. In summary, fluorescent studies on binding interactions between HSA and PpIX have been confirmed by the results of computer simulation. Keywords: photodynamic diagnosis; photodynamic therapy; protoporphyrin IX; human serum albumin; UV-VIS; emission fluorescence; molecular docking 1. Introduction The laser light affecting tissues can be used in the treatment of cancers and pre-cancerous lesions. An illumination initiates a photochemical reaction leading to the formation of cytotoxic compounds, which induce cell death [1,2]. Damage of the mitochondrial membrane, liposomes, Golgi apparatus, cytoplasmatic reticulum and nuclear membrane has been observed. This reaction cannot occur without a photosensitizer [3,4]. Photodynamic diagnosis (PDD) and therapy (PDT) take advantage of this phenomenon. The prevalence of the photodynamic reaction in neoplasm tissue and its surroundings is essential. PDD and PDT of cancer and pre-cancerous lesions require photosensitizers, which are activated by light [1,4]. Any particular photosensitizer cannot be highly effective in the treatment of different neoplasms. Its effectiveness depends on the chemical structure, lipo- or hydro-phobic properties, carrier and solvent, type of neoplasm, pH of intracellular and extracellular fluid, concentration of photosensitizer and the type of complexes formed with carriers. Molecules 2016, 21, 1519; doi:10.3390/molecules21111519 www.mdpi.com/journal/molecules Molecules 2016, 21, 1519 2 of 19 The porphyrin is a macrocycle composed of four pyrrole rings bridged by four sp2 hybridized carbon atoms [2,5]. Protoporphyrin IX (PpIX) is a clinically useful hydrophobic photosensitizer, which accumulatesMolecules the2016, lipid21, 1519 structures of cancer cells. PpIX is a heme metabolite [1,6,7]. PpIX is used2 of 19 in both PDD and PDT.The porphyrin is a macrocycle composed of four pyrrole rings bridged by four sp2 hybridized Sincecarbon human atoms serum[2,5]. Protoporphyrin albumin (HSA) IX (PpIX) is a component is a clinically of useful the circulatory hydrophobic system photosensitizer, [8], the understanding which of porphyrinaccumulates binding the lipid to HSA structures is crucial of cancer for PDD cells. and PpIX PDT is a successheme metabolite [5,9,10]. [1,6,7]. PpIX is used in Oneboth of PDD the and most PDT. important properties of HSA is its ability to bind and transport many endo- and exo-genic compounds,Since human serum which albumin have no(HSA) designed is a component transport of the proteins. circulatory Nevertheless, system [8], the compounds understanding having specificof transportporphyrin proteinsbinding to can HSA also is becrucial transported for PDD and by HSA.PDT success The formation [5,9,10]. of albumin-ligand complexes One of the most important properties of HSA is its ability to bind and transport many endo- and in the blood serum preserves ligands against oxidation, reduces their toxicity and improves their exo-genic compounds, which have no designed transport proteins. Nevertheless, compounds having solubility,specific and transport therefore, proteins the formationcan also be transported of the complexes by HSA. improvesThe formation the of transportation albumin-ligand ofcomplexes ligands. Preclinicalin the blood studies serum preserves are crucial ligands in order against to oxidat supportion, andreduces develop their toxicity PDD andand improves PDT. In ourtheir study, absorptionsolubility, and and fluorescence therefore, the UV formation spectroscopy of the complexes was used improves to find the PpIX transportation binding of sites ligands. in transporting protein tertiaryPreclinical structure. studies Molecularare crucial in docking order to was support applied and develop to check PDD and and confirm PDT. In our our experimental study, study.absorption The CLC and Drug fluorescence Discovery UV Workbench spectroscopy (CLC was DDWB) used to find molecular PpIX binding docking sites computer in transporting program is an integratedprotein tertiary virtual structure. environment Molecular for exploringdocking was various applied biochemical to check and processes,confirm our such experimental as binding of study. The CLC Drug Discovery Workbench (CLC DDWB) molecular docking computer program is small molecules (medicines, hormones, vitamins or minerals) to bioactive macromolecules (carrier an integrated virtual environment for exploring various biochemical processes, such as binding of proteins,small receptors molecules or (medicines, nucleic acids). hormones, Inthe vitamins study, or molecular minerals) to docking bioactive simulation macromolecules was (carrier used for the simulationproteins, of bindingreceptors interactions or nucleic acids). between In the the study, macromolecule molecular docking of HSA simulation and the moleculewas used for of PpIX.the simulation of binding interactions between the macromolecule of HSA and the molecule of PpIX. 2. Results and Discussion 2. Results and Discussion 2.1. Formation of the PpIX-HSA Complex 2.1. Formation of the PpIX-HSA Complex The absorption spectra of HSA (I), PpIX (II), as well as the PpIX-HSA system (III) are shown in Figure1The. Difference absorption spectra spectra of (III HSA− (I),I and PpIX III (II),− asII) well were as the also PpIX-HSA recorded. system The (III) absorption are shown spectrum in (I + II)Figure that arose1. Difference by the spectra addition (III of− I spectraand III − of II) PpIX were andalso recorded. HSA does The not absorption overlap spectrum the spectrum (I + II) of the that arose by the addition of spectra of PpIX and HSA does not overlap the spectrum of the complex complex (III). Similarly, difference spectra (III − I) and (III − II) do not overlap spectra (II) and (I), (III). Similarly, difference spectra (III − I) and (III − II) do not overlap spectra (II) and (I), respectively. respectively.A new quality A new in quality the PpIX-HSA in the PpIX-HSA system appeared. system This appeared. suggests This that suggestsa complex that between a complex HSA and between HSA andPpIX PpIX may be may formed. be formed. Figure 1. Difference spectra of protoporphyrin IX (PpIX) (5 × 10−6 M)-human serum albumin (HSA) Figure 1. Difference spectra of protoporphyrin IX (PpIX) (5 × 10−6 M)-human serum albumin (HSA) (1 × 10−6 M) systems. (1 × 10−6 M) systems. To obtain evidence of the complex formation between HSA and PpIX, fluorescence analysis Towas obtain conducted. evidence of the complex formation between HSA and PpIX, fluorescence analysis was conducted. Molecules 2016, 21, 1519 3 of 19 TheMolecules fluorescence 2016, 21, 1519 of HSA excited at both wavelength λex = 280 nm and 295 nm was quenched3 of 19 by PpIXMolecules (Figure 2016, 221)., 1519 The fluorescence of HSA excited at both λex = 280 nm and 295 nm decreased3 of 19 in The fluorescence of HSA excited at both wavelength λex = 280 nm and 295 nm was quenched by the presence of PpIX (Figure2). A hypsochromic shift of the HSA maximum emission fluorescence PpIX (Figure 2). The fluorescence of HSA excited at both λex = 280 nm and 295 nm decreased in the λ The fluorescence of HSA excited at both wavelength λex = 280 nm and 295 nm was quenched by at expresence= 334 andof PpIX 340 (Figure nm by 2). 7 A and hypsochromic 5 nm, respectively, shift of the is HSA observed. maximum The emission quenching fluorescence effect of at PpIX PpIX (Figure 2). The fluorescence of HSA excited at both λex = 280 nm and 295 nm decreased in the on theλex fluorescence= 334 and 340 ofnm HSA by 7 increasesand 5 nm, respectively, with increasing is observed. concentration The quenching of the effect ligand. of PpIX The on quenching
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