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Background: FMSP is a synthesized ferrocene derivative which possesses strong anti-proliferative and apoptosis inducing characteristics on tumor cells. Naringenin as a polyphenolic flavonoid is also able to reduce cell viability in tumors.Methods: Cell viability and proliferation of cancer cells after treatment with these agents were determined with MTT assay. To predict the possible interaction between calmodulin (CaM) and FMSP and naringenin, docking stuies were performed. By using fluorescence emission spectra, effects of FMSP and naringenin on CaM structure and activity were studied. CaM-dependent activation of phosphodiesterase 1 (PDE1) by FMSP in relation to naringenin and their combination were compared. Effects of these compounds on PDE1 inhibition, cAMP accumulation, and cAMP-dependent protein kinase A (PKA) activation were assayed. Results: Our results showed that combination of FMSP and naringenin had more inhibitory effects on CaM structure than FMSP and naringenin alone. Results of docking analyses also confirmed efficient intraction of the two compunds with hydrophobic pocket of calmodulin active site. Kinetic analyses of these agents interaction with CaM showed FMSP and naringenin both competitively inhibited PDE1 activation without changing Vmax parameter. FMSP and naringenin synergistically increased Km values in a higher level compared to FMSP or naringenin alone. Combination of these two agents also had more cytotoxic effects on K562 cells than FMSP alone. Conclusions: It was shown that mechanism of K562 cell proliferation inhibition by these compounds is based on CaM and consequent PDE inhibition followed by intracellular cAMP level elevation and increased PKA activity in a dose-dependent manner.

Background: Curcumin is a natural polyphenolic compound with anti-cancer, antiinflammatory, and anti-oxidation properties. Low water solubility and rapid hydrolytic degradation are two challenges limiting use of curcumin. Objective: In this study, the roles of the native/modified forms of Bovine Serum Albumin (BSA), β-lactoglobulin (β-lg) and casein, as food-grade biopolymers and also protein chemical modification, in stabilizing and on biological activity of curcumin were surveyed. Methods: In this article, we used various spectroscopic as well as cell culture-based techniques along with calculation of thermodynamic parameters. Results: Investigation of curcumin stability indicated that curcumin binding to the native BSA and modified β -lg were stronger than those of the modified BSA and native β -lg, respectively and hence, the native BSA and modified β-lg could suppress water-mediated and light-mediated curcumin degradation, significantly. Moreover, in the presence of the native proteins (BSA and casein), curcumin revealed elevated in vitro anti-cancer activity against MCF-7 (human breast carcinoma cell line) and SKNMC (human neuroblastoma cell line). As well, curcumin, in the presence of the unmodified “BSA and β-lg”, was more potent to decrease ROS generation by hydrogen peroxide (H2O2) whereas it led to an inverse outcome in the presence of native casein. Overall, in the presence of the protein-bound curcumin, increased anti-cancer activity and decreased ROS generation by H2O2 in vitro were documented. Conclusion: It appears that “water exclusion” is major determinant factor for increased stability/ efficacy of the bound curcumin so that some protein-curcumin systems may provide novel tools to increase both food quality and the bioavailability of curcumin as health promoting agent.

In recent years, concerns have been raised considering the potential risks of nanocluster (NC) for the environment and human health. Since the blood circulation system is probably the first entry route of NC into the human body, adsorption of blood proteins on NC may change cellular responses, including cellular uptake efficiency, bio distribution patterns, and nanotoxicity profiles, besides other biological effects. Therefore, the interaction of NCs with proteins and the cellular implications can be therapeutically of great importance. Adsorption of human blood proteins on NCs has been methodically investigated. In the present study, the first analysis of fibrillation was conducted between MBI-AgNCs and human serum (a complex biofluid). AgNCs were prepared by coating with 2-mercaptobenzimidazole. Then, interactions with human blood proteins, such as immunoglobulin, albumin, and insulin were investigated using various experimental approaches. Upon protein association, the fluorescence of proteins significantly decreased, accompanied by a blue shift in the AgNCs-human serum albumin (HSA) system and a red shift in the AgNCs-insulin/γ-globulin. Concomitantly, circular dichroism spectroscopy and atomic force microscopy were employed to investigate the effects of protein binding to NCs. We found that AgNCs induced γ-globulin aggregation. HSA at the AgNC surface was partially unfolded and could promote protein self-assembly into amyloid fibrils, while the surface morphology remained unchanged after insulin incubation. The atomic force microscopy (AFM) data and the ThT and CR analysis of the proteins, as well as circular dichroism (CD) and fluorescence findings, support the use of AgNCs as an indicator for monitoring the progress of HSA fibrillogenesis. Additionally, cytotoxicity assays were used to ensure the biocompatibility of nanoparticles within the applicable limits.

The aggregation of Tau into amyloid fibrils is a hallmark of neurodegenerative diseases such as Alzheimer's disease (AD). Compared to the Aβ peptide, tau pathology more closely tracks changes in brain function that are responsible for the onset of early symptoms in AD. Tau belongs to the class of intrinsically disordered protein and folds into an ordered β-structure during aggregation, a process that appears in many cases to be preceded by hyperphosphorylation of Tau monomers. Although Tau fibrils can be formed by heparin-induced aggregation of un-phosphorylated recombinant Tau, it is important to understanding the paradox of Tau's random-like conformations and aggregation propensity. In this study, to look into the effect of charge neutralization on Tau aggregation propensity, solvent accessible lysine residues were chemically acetylated/pseudo-phosphorylated. All Tau variants did not aggregate in the absence of the polyanionic factor; however, in contrast to the wild-type protein, acetylated and pseudo-phosphorylated variants were not able to aggregate even in the presence of the polyanionic cofactor. These aggregation incompetent Tau variants may be good analogs for the phosphorylated Tau, to explore more about the exact role of the phosphorylated Tau monomers in AD progress.

In this report, the effect of topiramate (TPM), an anticonvulsant sulfamate drug, on the structure of human carbonic anhydrase II (hCA II) was investigated by spectroscopic techniques. The intrinsic fluorescence experiments indicated that TPM binding causes enhancement of enzyme fluorescence via decreasing the internal quenching and energy transfer efficiency, the result supported by molecular dynamics simulation. Thermodynamic analysis of the binding process suggested that hydrogen bonding and van der Waals interactions are the major forces in the interaction of TPM with hCA II. The far-UV circular dichroism (CD) results showed that TPM caused increment in α-helical and β-sheet content of hCA II whereas, near-UV CD experiments in the presence of the drug showed induction of some compactness in the enzyme tertiary structure. The number of accessible tryptophans and protein surface hydrophobicity index of the enzyme were reduced in the presence of TPM which confirms the enzyme structural compactness upon drug binding. In addition, the enzyme thermal stability was increased in the presence of the drug. It seems that the induction of compactness in the enzyme structure upon drug binding may be responsible for increment of its conformational stability.

In the recent years, tamoxifen has been often co-administrated with estradiol to treatment of breast cancer. Hence, we examined the interaction of two anti-breast cancer drugs, tamoxifen and estradiol, with human serum albumin (HSA) using spectroscopic and molecular modeling techniques. The quenching of intrinsic fluorescence and docking were used to calculate binding affinity and location, while the RLS, synchronous fluorescence and CD spectroscopy were done to investigate the effect of these drugs on protein conformational changes, both separately and simultaneously. While the photo-stability of drugs increased in the presence HSA, the enhancement of RLS intensity was attributed to the formation of a new complex between the two drugs and the protein. Both drugs showed a strong ability to quench the fluorescence of HSA via static mechanism. The fluorescence quenching action at different temperatures and enhancement of RLS intensity were much stronger when the two drugs co-existed, whereas the binding affinity of both drugs were partially affected by each other, which demonstrate that two drugs bind to distinct/different location on HSA via hydrophobic interactions. On the other hand, appearance of new peak at 405 nm accompanying with quenching of HSA fluorescence at 340 nm by tamoxifen revealed that the drug binds near the protein Trp residue in subdomain IIA, which confirmed the docking results. Furthermore, synchronous fluorescence and CD data clearly indicate that the conformation of HSA was changed upon addition of the drugs which can affect the physiological functions of HSA and binding of other drugs.

Albumin which is the most abundant drug carrier protein in plasma controls the distribution aspect of drug pharmacokinetics. The aim of this study has been to elucidate the concurrent binding behavior of indomethacin/ibuprofen/heme to HSA under the effect of aspirin-mediated protein acetylation and also to explore the esterase-like catalytic property of the unmodified/modified proteins, as binary or ternary systems, by using various spectroscopic and molecular docking techniques. We found that aspirin-based modification of HSA affects the protein conformation as well as ligand binding at sites I–III. Decrease in pNPA-mediated esterase activity of HSA in different reversible inhibition modes, upon the protein–ligand interactions, was also documented, an issue that may receive considerable attention for computational prodrug design in near future.

Ferritin is a giant protein composed of 24 subunits which is able to sequester up to 4500 atoms of iron. We proposed two kinds of heme binding sites in mammalian ferritins and provided direct evidence for peroxidase activity of heme-ferritin, since there is the possibility that "ferritin-heme" systems display unexpected catalytic behavior like heme-containing enzymes. In the current study, peroxidase activity of heme-bound ferritin was studied using TMB(1), l-DOPA, serotonin, and dopamine, in the presence of H2O2, as oxidant substrate. The catalytic oxidation of TMB was consistent with first-order kinetics with respect to ferritin concentration. Perturbation of the binding affinity and catalytic behavior of heme-bound His-modified ferritin were also documented. We also discuss the importance of the peroxidase-/nitrative-mediated oxidation of vital molecules as well as ferritin-induced catalase inhibition using in vitro experimental system. Uncontrollable "heme-ferritin"-based enzyme activity as well as up-regulation of heme and ferritin may inspire that some oxidative stress-mediated cytotoxic effects in AD-affected cells could be correlated to ferritin-heme interaction and/or ferritin-induced catalase inhibition and describe its contribution as an important causative pathogenesis mechanism in some neurodegenerative disorders.

Heme and bilirubin (BR), as by-products of red blood cells (and hemoglobin) degradation, show increased plasma concentrations in some diseases. These two toxic hydrophobic molecules are mainly transported in the blood-stream by human serum albumin (HSA) that carries a wide variety of ligands. Under normal physiological conditions, ~3 fatty acid (FA) molecules are bound to each HSA; and its possible effect on BR/heme binding remains to be more clarified. In the present study, to provide deeper insight on this issue, we purified albumin from healthy individuals (as purified non-defatted albumin or PA) with normal plasma levels of FA, then defatted some of the purified protein (as defatted-HSA; or DA). In the next step, using various spectroscopic methods, their interactions with heme and BR were investigated. By 1: 1 binding of the ligands, quenching and thermodynamic analysis of parameters indicated that binding constants (Kb) values of bilirubin and heme for PA and DA are different. It could be perceived that the presence of FAs in high-affinity FA binding sites (FABSs) exerted considerable conformational changes in the structure followed by an improved BR binding while hindered heme interaction. The data was confirmed by determining surface hydrophobicity of the purified albumin (PA) and DA, and then supported by bioinformatics analyses. The physiological and clinical relevance of the observed dynamic interactions is also discussed. This study, also, re-confirmed that the primary BR binding site is subdomain IIA not subdomain IB.

Human serum albumin (HSA), the most abundant protein in blood plasma, is a monomeric multidomain protein that possesses an extraordinary capacity for binding, so that serves as a circulating depot for endogenous and exogenous compounds. During the heat sterilization process, the structure of pharmaceutical-grade HSA may change and some of its activities may be lost. In this study, to provide deeper insight on this issue, we investigated drug-binding and some physicochemical properties of purified albumin (PA) and pharmaceutical-grade albumin (PGA) using two known drugs (indomethacin and ibuprofen). PGA displayed significantly lower drug binding capacity compared to PA. Analysis of the quenching and thermodynamic parameters indicated that intermolecular interactions between the drugs and the proteins are different from each other. Surface hydrophobicity as well as the stability of PGA decreased compared to PA, also surface hydrophobicity of PA and PGA increased upon drugs binding. Also, kinetic analysis of pseudo-esterase activities indicated that Km and Vmax parameters for PGA enzymatic activity are more and less than those of PA, respectively. This in vitro study demonstrates that the specific drug binding of PGA is significantly reduced. Such studies can act as connecting bridge between basic research discoveries and clinical applications.

Amyloid states of many proteins complex with heme and exhibit significant non-specific peroxidase activity, compared to free heme. Neurotransmitter deficiency, generation of neurotoxins, altered activity/metabolism of key enzymes and cellular DNA damage are possible evidences highlighting the importance of the uncontrollable peroxidase activity in Alzheimer's disease (AD)-involved brain cells. Despite extensive experimental work was carried out on this field, discrepancy on chronological precedence of amyloid aggregation and oxidative reactions as well as the mechanism involved in the peroxidase-induced oxidative stress is still not completely understood. In this study, we highlight further that heme cofactor readily complexes with structural intermediates of amyloid aggregates of ovalbumin, lactoglobulin and crystallin and report the ability of "heme-amyloid aggregate/oligomer") to produce peroxidase-like active site. Histidine side chains are also proposed as both distal and proximal residues required for proper function of these peroxidase systems. Taking uncontrollable peroxidase activity of "Aβ-heme" complex into account, it appears that this process, as a new opened dimension in AD pathologic research, provides structural/mechanistic basis for more efficient therapeutic strategies against neurodegenerative diseases.

Human serum albumin (HSA) is the most prominent extracellular protein in blood plasma. There are several binding sites on the protein which provide accommodation for structurally-unrelated endogenous and exogenous ligands and a wide variety of drugs. “Esterase-like” activity (hydrolysis of p-nitrophenyl esters) by the protein has been also reported. In the current study, we set out to investigate the interaction of indomethacin and ibuprofen with the unmodified and modified HSA ( p NPA-modified HSA) using various spectroscopic techniques. Fluorescence data showed that 1:1 binding of drug to HSA is associated with quenching of the protein intrinsic fluorescence. Decrease of protein surface hydrophobicity (PSH), alteration in drug binding affinity and change of the protein stability, after esterase-like activity and permanent acetylation of HSA, were also documented. Analysis of the quenching and thermodynamic parameters indicated that forces involved in drug–HSA interactions change upon the protein modification.

Human serum albumin (HSA)-drug binding affinity is one of the major factors that determine the pharmacokinetics, halftime and bioavailability of drugs in various tissues. In the present study, the interaction of olanzapine (OLZ), a thienobenzodiazepine drug, administered for the treatment of schizophrenia and bipolar disorder, with HSA has been studied using spectroscopic methods such as ultraviolet absorbance, fluorescence and FTIR combined with computational procedures. Analyzing of the Stern–Volmer quenching data showed only one primary binding site on HSA with a binding constant of 4.12×10 4 M −1 at 298 K. Thermodynamic analyses showed enthalpy change (Δ H °) and entropy change (Δ S °) were 28.03±3.42 kJ mol −1 and −25.52±11.52 J mol −1 K −1 , respectively. Molecular docking results suggested the hydrophobic residues such as Val 216 , Leu 327 , Ala 350 and polar residues such as Glu 354 play an important role in the drug binding. Decrement in α-helix content of the protein upon OLZ binding was also confirmed by evidences provided by molecular dynamics simulation as well as FTIR spectroscopy.

In the present research, the binding properties of diazinon (DZN), as an organophosphorus herbicide, to human serum albumin (HSA) were investigated using combination of spectroscopic, electrochemistry, and molecular modeling techniques. Changes in the UV-Vis and FT-IR spectra were observed upon ligand binding along with a significant degree of tryptophan fluorescence quenching on complex formation. The obtained results from spectroscopic and electrochemistry experiments along with the computational studies suggest that DZN binds to residues located in subdomains IIA of HSA with binding constant about 1410.9 M

Curcumin is a natural polyphenolic compound with anticancer, anti-inflammatory, and antioxidation properties. Low water solubility and rapid hydrolytic degradation are two challenges limiting use of curcumin. In this study, the role of the native/modified forms of bovine serum albumin and casein, as food-grade biopolymers and safe drug delivery systems and also protein chemical modification in stabilizing of curcumin were surveyed. Investigation on curcumin stability indicated that curcumin binding to the native bovine serum albumin is stronger than the modified bovine serum albumin, and hence, native protein could suppress water-mediated curcumin degradation. Drug competitive binding, fluorescence resonance energy transfer, and molecular docking studies suggested that the binding site for curcumin has not been changed upon albumin modification. Moreover, different observations were made for both the native and modified caseins. It appears from thermodynamic analyses that in “protein-curcumin” systems, wa...

The studies on the interaction between human serum albumin (HSA) and drugs have been an interesting research field in life science, chemistry and clinical medicine. Osthole possesses a variety of pharmacological activities including anti-tumor, anti-inflammation, anti-seizure, anti-hyperlipidemic and anti-osteoporosis effects. The interaction of osthole with HSA and its binding site in HSA by spectroscopic methods is the subject of this work. By monitoring the intrinsic fluorescence of the single Trp214 residue and performing site markers displacement measurements, the specific binding of osthole in the vicinity of Sudlow's site I of HSA has been clarified. The changes in the secondary structure of HSA after its complexation with ligand were studied with CD spectroscopy, which indicate that osthole induced only a slight decrease in the helix structural content of the protein. In addition, the mean distance between osthole and HSA fluorophores is estimated to be 4.96 nm using Foster's equation on the basis of the fluorescence energy transfer. Furthermore, the synchronous fluorescence spectra show that the microenvironment of the tryptophan residues does not have obvious changes. Osthole can quench the intrinsic fluorescence of HSA by dynamic quenching, and analysis of the thermodynamic parameters of binding showed that hydrophobic interactions play an important role in the stabilizing of the complex. Increase of protein surface hydrophobicity (PSH) was also observed upon the osthole binding.

Isoimperatorin is one of the main components ofPrangos ferulaceaas a linear furanocoumarin and used as anti-inflammatory, analgesic, antispasmodic, and anticancer drug. Human serum albumin (HSA) is a principal extracellular protein with a high concentration in blood plasma and carrier for many drugs to different molecular targets. Since the carrying of drug by HSA may affect on its structure and action, we decided to investigate the interaction between HSA and isoimperatorin using fluorescence and UV spectroscopy. Fluorescence data indicated that isoimperatorin quenches the intrinsic fluorescence of the HSA via a static mechanism and hydrophobic interaction play the major role in the drug binding. The binding average distance between isoimperatorin and Trp 214 of HSA was estimated on the basis of the theory of Förster energy transfer. Decrease of protein surface hydrophobicity (PSH) was also documented upon isoimperatorin binding. Furthermore, the synchronous fluorescence spectra show that the microenvironment of the tryptophan residues does not have obvious changes. Site marker compettive and fluorescence experiments revealed that the binding of isoimperatorin to HSA occurred at or near site I. Finally, the binding details between isoimperatorin and HSA were further confirmed by molecular docking and esterase activity inhibition studies which revealed that drug was bound at subdomain IIA.

Purple acid phosphatases (PAPs) are binuclear metallo-hydrolases that have been isolated from various mammals, plants, fungi and bacteria. In mammals, PAP activity is associated with bone resorption and can lead to bone metabolic disorders such as osteoporosis; thus human PAP is an attractive target to develop anti-osteoporotic drugs. The aim of the present study was to investigate inhibitory effect of synthesized diethylalkylsulfonamido(4-methoxyphenyl)methyl)phosphonate/phosphonic acid derivatives as potential red kidney bean PAP (rkbPAP) inhibitors accompanied by experimental and molecular modeling assessments. Enzyme kinetic data showed that they are good rkbPAP inhibitors whose potencies improve with increasing alkyl chain length. Hexadecyl derivatives, as most potent compounds (Ki = 1.1 µM), inhibit rkbPAP in the mixed manner, while dodecyl derivatives act as efficient noncompetitive inhibitor. Also, analysis by molecular modeling of the structure of the rkbPAP–inhibitor complexes reveals factors, which may be important for the determination of inhibition specificity.

The inhibitory activity of captopril, a thiol-containing competitive inhibitor of the angiotensin-converting enzyme, ACE, against esterase activity of carbonic anhydrase, CA was investigated. This small molecule, as well as enalapril, was selected in order to represents both thiol and carboxylate, as two well-known metal binding functional groups of metalloprotein inhibitors. Since captopril, has also been observed to inhibit other metalloenzymes such as tyrosinase and metallo-beta lactamase through binding to the catalytic metal ions and regarding CA as a zinc-containing metallo-enzyme, in the current study, we set out to determine whether captopril/enalapril inhibit CA esterase activity of the purified human CA II or not? Then, we revealed the inhibitors' potencies (IC50, Ki and Kdiss values) and also mode of inhibition. Our results also showed that enalapril is more potent CA inhibitor than captopril. Since enalapril represents no sulfhydryl moiety, thus carboxylate group may have a determinant role in inhibiting of CA esterase activity, the conclusion confirmed by molecular docking studies. Additionally, since CA inhibitory potencies of captopril/enalapril were much lower than those of classic sulfonamide drugs, the findings of the current study may explain why these drugs exhibit no effective CA inhibition at the concentrations reached in vivo and also may shed light on the way of generating new class of inhibitors that will discriminately inhibit various CA isoforms.

In many neurodegenerative diseases, formation of protein fibrillar aggregates has been observed as a major pathological change. Neurofibrillary tangles, mainly composed of fibrils formed by the microtubule-associated protein; Tau, are a hallmark of a group of neurodegenerative diseases such as Alzheimer's disease. Tau belongs to the class of natively unfolded proteins and partially folds into an ordered β-structure during aggregation. Polyanionic cofactors such as heparin are commonly used as inducer of Tau aggregation in vitro. The role of heparin in nucleation and elongation steps during Tau fibril formation is not fully understood. In the current study, aggregation kinetics as well as structure of Tau amyloid fibrils, by using the 1N4R isoform, have been reproducibly determined in the presence of heparin and the shorter molecule; enoxaparin. The kinetic studies demonstrated that heparin (not enoxaparin) efficiently accelerates Tau amyloid formation and revealed, mechanistically, that the molecular weight of the inducer is important in accelerating amyloidogenesis. The kinetic parameter values of Tau amyloid aggregation, especially, the amyloid aggregation extent, were relatively different in the presence of heparin and enoxaparin, at various stoichiometries of the inducers binding. Also, based on the results, obtained from CD, FTIR, AFM and XRD studies, it may be suggested that the inducer length plays a critical role mainly in the nucleation process, so that it determines that oligomers lie on or off the pathway of Tau fibrillization. The biochemical results herein suggest that the chemical environment of the extracellular matrix as well as localization of distinct glycosaminoglycans may influence deposition behavior of Tau amyloidosis.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by aggregation of amyloid-β (Aβ) peptide, formation of neurofibrillary tangles, synaptic loss and neuronal cell death, and is manifested clinically by progressive cognitive dysfunction and memory loss. Disease pathogenesis is mainly linked to the formation of Aβ insoluble or soluble oligomeric assemblies. Binding of heme to Aβ has been suggested as the origin of the heme deficiency, peroxidase activity, as well as some oxidative stress-mediated AD pathologies, and then differential affinity of heme for human and rodent Aβ peptide has been proposed to account for the susceptibility of humans to AD. This review highlights whether there is any dependency of peroxidase activity of heme-bound Aβ on the Aβ aggregation state or not, with focusing on emerging role of heme in neurodegeneration. Here, several lines of evidence supporting existing contradictory conjectures are discussed.

Aldehyde oxidase (AO), a cytosolic molybdenum-containing hydroxylase, is predominantly active in liver and other tissues of mammalian species and involved in the metabolism of extensive range of aldehydes and nitrogen-containing compounds. A wide range of natural components including polyphenols are able to interfere with AO-catalyzed reactions. Polyphenols and flavonoids are one of the extensive secondary plant metabolites ubiquitously present in plants considered an important part of the human diet. The aim of the present study was to investigate inhibitory effect of selected phenolic compounds from three subclasses of aurone, flavanone and phenolic lactone compounds on the activity of AO, spectrophotometrically. AO enzyme was partially purified from liver of guinea pig. Then, inhibitory effects of 10 flavonoid compounds including 8 derivatives of 2-benzylidenebenzofuran-3(2H)-ones, as well as naringenin and ellagic acid on the activity of aldehyde oxidase were assessed compared with the specific inhibitor of AO, menadione. Among the phenolic compounds with inhibitory effects on the enzyme, ellagic acid (IC50=14.47 μM) was the most potent agent with higher inhibitory action than menadione (IC50=31.84 μM). The mechanisms by which flavonoid compounds inhibit AO activity have been also determined. The inhibitory process of the assessed compounds occurs via either a non-competitive or mixed mode. Although flavonoid compounds extensively present in the nature, mainly in dietary regimen, aurones with promising biological properties are not widely distributed in nature, so synthesis of aurone derivatives is of great importance. Additionally, aurones seem to provide a promising scaffold in medicinal chemistry for the skeleton of new developing drugs, so the results of the current study can be valuable in order to better understanding drug-food as well as drug-drug interaction and also appears to be worthwhile in drug development strategies.

Human serum albumin (HSA)-drug binding is an important factor to determine half life and bioavailability of drugs. In the present research, the interaction of sertraline (SER) to HSA was investigated using combination of spectroscopic and molecular modeling techniques. Changes in the UV-Vis, CD and FT-IR spectra as well as a significant degree of tryptophan fluorescence quenching were observed upon SER-HSA interaction. Data obtained by spectroscopic methods along with the computational studies suggest that SER binds to residues located in subdomain IIA of HSA. Analysis of spectroscopic data represented the formation of 1:1 complex, significant binding affinity, negative values of entropy and enthalpy changes and the essential role of hydrophobic interactions in binding of SER to HSA. The binding models were demonstrated in the aspects of SER's conformation, active site interactions, important amino acids and hydrogen bonding. Computational mapping of the possible binding site of SER confirmed that the ligand to be bound in a large hydrophobic cavity of HSA. In accordance with experimental data, computational analyses indicated that SER binding does not alter the secondary structure of the protein. The results not only lead to a better understanding of interaction between SER and HSA but also provide useful data about the influence of SER on the protein conformation.

The interaction between serum albumin (SA) and drugs has provided an interesting ground for understanding of drug effects, especially in drug distribution and drug-drug interaction on SA, in the case of multi-drug therapy. Determination of the impact of various factors on drug-protein interaction is especially important upon significant binding of drug to albumin. In the present study, the interaction of two drugs (furosemide and indomethacin) with native and modified albumins were investigated by using various spectroscopic methods. Fluorescence data indicated that 1:1 binding of drugs to bovine serum albumin (BSA) is associated with quenching of albumin intrinsic fluorescence. The Job's plot also confirmed that drug binds to BSA via mentioned stoichiometry. Analysis of the quenching and thermodynamic parameters indicated that intermolecular interactions between drug and albumin may change upon protein modification. The theoretical analyses also suggested some conformational changes of interacting side chains in subdomain IIA binding site (at the vicinity of W237), which were in good agreement with experimental data. Decrease of protein surface hydrophobicity (PSH) was also observed upon both albumin modification and drug binding.