Correction: In vitro and in vivo antiproliferative activity of organo-nickel SCS-pincer complexes on estrogen responsive MCF7 and MC4L2 breast cancer cells. Effects of amine fragment substitutions on BSA binding and cytotoxicity.

Correction for 'In vitro and in vivo antiproliferative activity of organo-nickel SCS-pincer complexes on estrogen responsive MCF7 and MC4L2 breast cancer cells. Effects of amine fragment substitutions on BSA binding and cytotoxicity' by Mahboubeh Hosseini-Kharat et al., Dalton Trans., 2018, 47, 16944-16957, https://doi.org/10.1039/c8dt03079k.

Mode of binding, kinetic and thermodynamic properties of a lipid-like drug (Fingolimod) interacting with Human Serum Albumin.

Introduction: Fingolimod is a drug that is used to treat multiple sclerosis (MS). It has pH-dependent solubility and low solubility when buffering agents are present. Multi-spectroscopic and molecular modeling methods were used to investigate the molecular mechanism of Fingolimod interaction with human serum albumin (HSA), and the resulting data were fitted to the appropriate models to investigate the molecular mechanism of interaction, binding constant, and thermodynamic properties. Methods: The interaction of Fingolimod with HSA was investigated in a NaCl aqueous solution (0.1 mM). The working solutions had a pH of 6.5. Data was collected using UV-vis, fluorescence quenching titrations, FTIR, and molecular modeling methods. Results: According to the results of the fluorescence quenching titrations, the quenching mechanism is static. The apparent binding constant value (KA = 4.26×103) showed that Fingolimod is a moderate HSA binder. The reduction of the KA at higher temperatures could be a result of protein unfolding. Hydrogen bonding and van der Waals interactions are the main contributors to Fingolimod-HSA complex formation. FTIR and CD characterizations suggested a slight decrease in the α-helix and ß-sheets of the secondary structure of HSA due to Fingolimod binding. Fingolimod binds to the binding site II, while a smaller tendency to the binding site I was observed as well. The results of the site marker competitive experiment and the thermodynamic studies agreed with the results of the molecular docking. Conclusion: The pharmacokinetic properties of fingolimod can be influenced by its HSA binding. In addition, considering its mild interaction, site II binding drugs are likely to compete. The methodology described here may be used to investigate the molecular mechanism of HSA interaction with lipid-like drugs with low aqueous solubility or pH-dependent solubility.

Study of ß-lactam-based drug interaction with albumin protein using optical, sensing, and docking methods.

The quality and strength of drug and albumin interaction affecting the drug-free concentration and physiological activity are important issues in pharmacokinetic research. In the present study, not only did we evaluate the binding strength of ceftriaxone and ceftizoxime to bovine serum albumin (BSA), but we also investigated the kinetic and thermodynamic parameters including KD, KA, ΔS, and ΔH. We applied in vitro optical fluorescence spectroscopy and surface plasmon resonance (SPR) sensing approaches as well as molecular docking analyses. The kinetic and thermodynamic investigations were done using different concentrations of drugs at three temperatures. Thermodynamic parameters visibly demonstrated that the binding was an exothermic and spontaneous process. The obtained negative values of both enthalpy change (ΔH) and entropy change (ΔS) in fluorescence and SPR and also molecular docking investigations showed that the major binding force involved in the complexation of drugs to BSA was hydrogen bonding. Static quenching was the foremost fluorescence quenching mechanism between them. Furthermore, the results of ΔG and KD values proved that the interaction of ceftriaxone-BSA was stronger than ceftizoxime-BSA. Finally, molecular docking confirmed that the preferable binding sites of ceftizoxime and ceftriaxone were site IIA and site IB of albumin, respectively.

The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach.

The novel coronavirus disease (COVID-19) is currently a big concern around the world. Recent reports show that the disease severity and mortality of COVID-19 infected patients may vary from gender to gender with a very high risk of death for seniors. In addition, some steroid structures have been reported to affect coronavirus, SARS-CoV-2, function and activity. The entry of SARS-CoV-2 into host cells depends on the binding of coronavirus spike protein to angiotensin converting enzyme-2 (ACE2). Viral main protease is essential for the replication of SARS-CoV-2. It was hypothesized that steroid molecules (e.g., estradiol, progesterone, testosterone, dexamethasone, hydrocortisone, prednisone and calcitriol) could occupy the active site of the protease and could alter the interaction of spike protein with ACE2. Computational data showed that estradiol interacted more strongly with the main protease active site. In the presence of calcitriol, the binding energy of the spike protein to ACE2 was increased, and transferring Apo to Locked S conformer of spike trimer was facilitated. Together, the interaction between spike protein and ACE2 can be disrupted by calcitriol. Potential use of estradiol and calcitriol to reduce virus invasion and replication needs clinical investigation.

Investigations of the molecular mechanism of diltiazem binding to human serum albumin in the presence of metal ions, glucose and urea.

The molecular mechanism and thermodynamic properties of the interaction between diltiazem (DTZ) and human serum albumin (HSA), has been studied in vitro using spectroscopic techniques (UV-Vis, fluorescence, FTIR), and molecular docking methods. The effect of acidic and basic pH, glucose, urea, and metal ions on the DTZ-HSA binding has been investigated as well. According to the results, there is a 1:1 interaction between DTZ and HSA, while the quenching mechanism is static up to 313 K. The apparent binding constant was 2.09 × 106 M-1 that indicates a strong binding between DTZ and HSA. DTZ binding was increased in acidic pH while its binding was slowly decreased in the presence of glucose, urea, and metal ions. Thermodynamic studies showed that DTZ binds to HSA via an exothermic and spontaneous reaction via hydrogen bonding and electrostatic interactions. The conformational alteration of HSA is obvious according to the FTIR study. The site marker competitive study confirmed the binding of DTZ to the warfarin binding site. Molecular docking studies showed that DTZ binds to subdomain IB (-9.22 kcal mol-1) and subdomain IIIA (-9.03 kcal mol-1) with a higher tendency. Also, the results showed that the oxygen and nitrogen atoms of hydroxyl and amino functional groups of DTZ facilitate hydrogen bond formation. HighlightsStrong binding of diltiazem to HSA was studied and confirmed by fluorescence quenching titrations.Diltiazem binding to HSA reduces in the presence of metal ions, glucose, urea and alkaline pH.Diltiazem binding to HSA is exothermic and spontaneous.

Molecular mechanism and thermodynamic study of Rosuvastatin interaction with human serum albumin using a surface plasmon resonance method combined with a multi-spectroscopic, and molecular modeling approach.

Rosuvastatin (ROS) is an anti-cholesterol drug belonging to statin drugs. A multi-spectroscopic approach combined with a molecular modeling technique was used to assess ROS association with human serum albumin (HSA). Besides, an HSA immobilized surface plasmon resonance (SPR) chip was used to obtain kinetic parameters (ka, kd, and KD). Fluorescence quenching titrations revealed that ROS interacts with HSA via a dynamic, exothermic, enthalpy-driven mechanism. Hydrogen bonds and van der Waals interactions as the most prevalent bonding forces contribute to ROS-HSA complex formation. ROS binding to HSA alters HSA conformation. The SPR results indicated that ROS and HSA have a strong interaction possessing an equilibrium constant (KD) of 1.55 × 10-8 M at 298 K. A competitive analysis of site markers showed that ROS has a higher tendency to bind to the warfarin binding site (site IIA), which may explain why warfarin has a higher anticoagulant effect in ROS users. FRET analysis indicated that non-radiation energy transfer occurred between ROS and HSA. According to molecular docking studies, ROS prefers binding sites IB and IIA while the ROS-HSA complex stabilizes due to the hydrogen bond and π-π interaction. The presence of hydrogen-bond donors and acceptors, as well as aromatic ROS moieties, facilitates such interactions.

Engineering of Ocriplasmin Variants by Bioinformatics Methods for the Reduction of Proteolytic and Autolytic Activities.

Background: Ocriplasmin has been developed for the induction of posterior vitreous detachment in patients with vitreomacular adhesion. At physiological pH, ocriplasmin is susceptible to autolytic and proteolytic degradation, limiting its activity duration. These undesirable properties of ocriplasmin can be reduced by site-directed mutagenesis, so that its enzymatic activities can be augmented. This study aimed to design ocriplasmin variants with improved biological/physicochemical characteristics via bioinformatics tools. Methods: This study was performed in Tabriz University of Medical Sciences, Tabriz, Iran, 2019. Through site-directed mutagenesis, three ocriplasmin variants were designed. Structural analysis was performed on the wild-type variant and the mutant variants using the Protein Interactions Calculator (PIC) server. The interactions between the S-2403 substrate and the ocriplasmin variants were studied by molecular docking simulations, and binding capability was evaluated by the calculation of free binding energy. The conformational features of protein-substrate complex systems for all the variants were evaluated using molecular dynamic simulations at 100 nanoseconds. Results: The structural analysis of ocriplasmin revealed that the substitution of threonine for alanine 59 significantly reduced proteolytic activity, while the substitution of glutamic acid for lysine 156 influenced autolytic function. The molecular docking simulation results indicated the appropriate binding of the substrate to the ocriplasmin variants with high-to-low affinities. The binding affinity of the wild-type variant for the substrate was higher than that between the mutant variants and the substrate. Simulation analyses, consisting of the root-mean-square deviation, the root-mean-square fluctuation, and the center-of-mass average distance showed a higher affinity of the substrate for the wild type than for the mutant variants. Conclusion: The mutational analysis of ocriplasmin revealed that A59T and K156E mutagenesis could be used for the development of a new variant with higher therapeutic efficacy.

Experimental and theoretical studies of Palladium-hydrazide complexes' interaction with DNA and BSA, in vitro cytotoxicity activity and plasmid cleavage ability.

New palladium complexes with general formula trans-[Pd(L)2(OAc)2] (1,2), (L = Benzhydrazide and 2-Furoic hydrazide) have been synthesized and characterized with various methods including elemental analysis, FT-IR, 1HNMR and mass spectroscopy. Afterward their interactions with bovine serum albumin and calf thymus deoxyribonucleic acid have been investigated by UV-vis absorption, fluorescence emission and circular dichroism spectroscopy. Also, site-selective replacement experiments with site probes have been carried out. Analysis of fluorescence spectrum indicated static quenching mechanism. Spectroscopic measurements for DNA binding showed the groove binding to DNA for both complexes. Furthermore, cytotoxicity studies of complexes and cis-platin have been done against colon carcinoma (CT26) and breast cancer (4T1) cell lines. Evaluation of complexes (1) and (2) on induction of apoptosis in CT26 cells has been done. Finally, plasmid cleavage ability of (1) and (2) was investigated by gel electrophoresis that indicate the more activity of (1) than (2).

In vitro and in vivo antiproliferative activity of organo-nickel SCS-pincer complexes on estrogen responsive MCF7 and MC4L2 breast cancer cells. Effects of amine fragment substitutions on BSA binding and cytotoxicity.

A family of organonickel complexes has been prepared, fully characterized, and tested for their antiproliferative activity against estrogen-responsive human breast cancer cells (MCF7). The three SCS-type pincer ligands HL1, HL2, and HL3 and their corresponding Ni(ii) complexes NiL1, NiL2, and NiL3 have been synthesized and fully characterized, including by single crystal diffraction studies for the complexes. The complexes possess square planar geometry with two symmetrical 5-membered nickellacycles. Fluorescence spectroscopy, circular dichroism measurements, molecular modeling, colorimetric based assay and tumor transplantation studies were used to evaluate the protein binding and antiproliferative activities of these organometallic complexes both in vitro and in vivo. Fluorescence quenching was used to investigate bovine serum albumin (BSA) interaction at different temperatures (293, 303 and 313 K), and the results were analyzed using the classical Stern-Volmer equation, allowing us to propose a dynamic quenching mechanism. Studies in vitro on the antiproliferative activity of the three organonickel complexes against estrogen-responsive human breast cancer cells (MCF7) showed promising antitumor activity for NiL1 containing pyrrolidine fragments. In vivo administration of this compound significantly inhibits tumor growth in estrogen-dependent MC4L2 cancer cells in female BALB/c mice.

Bovine serum albumin binding study to erlotinib using surface plasmon resonance and molecular docking methods.

Bovine serum albumin (BSA) is the most abundant protein in the blood circulation and it is commonly used for drug delivery in blood. Therefore, we aim to study BSA interaction with erlotinib as an anticancer drug using surface plasmon resonance (SPR) and molecular modeling methods under physiological conditions (pH = 7.4). BSA immobilized on carboxymethyl dextran hydrogel Au chip (CMD) after activation with N-hydroxysuccinimide and N-ethyl-N-(3-diethylaminopropyl) carbodiimide and then the erlotinib binding to BSA at different concentrations was evaluated. Increasing of erlotinib concentration led to dose-response sensorgrams of BSA. The amount of equilibrium constant (KD) at 25 °C (4.25 × 10-9) showed the high affinity of erlotinib to BSA. Thermodynamic parameters were attained at four different temperatures. The positive value of enthalpy and entropy showed that hydrophobic forces play major role in the interaction of erlotinib with BSA. Besides, the positive value of Gibbs free energy demonstrated that the interaction of erlotinib with BSA was nonspontaneous and enthalpy driven and the complexion of drug were dependent on endothermic process. According to the molecular docking study, the most favorable binding sites of erlotinib on the BSA were subdomain IIIA and IB. Moreover, molecular docking study results showed that hydrogen binding has a role in intermolecular force that stabilize erlotinib-BSA complex.

Surface plasmon resonance and molecular docking studies of bovine serum albumin interaction with neomycin: kinetic and thermodynamic analysis.

Introduction: The interactions between biomacromolecules such as serum albumin (SA) and various drugs have attracted increasing research attention in recent years. However, the study of SA with those drugs that have relatively high hydrophilicity and a lower affinity for SA could be a challenging issue. At the present study, the interaction of bovine SA (BSA) with neomycin as a hydrophilic drug has been investigated using surface plasmon resonance (SPR) and molecular docking methods. Methods: BSA was immobilized on the carboxymethyl dextran hydrogel sensor chip after activation of carboxylic groups through NHS/EDC and, then, the neomycin interaction with BSA at different concentrations (1-128 µM) was investigated. Results: Dose-response sensorgrams of BSA upon increasing concentration of neomycin has been shown through SPR analysis. The small KD value (4.96 e-7 at 40°C) demonstrated high affinity of neomycin to BSA. Thermodynamic parameters were calculated through van't Hoff equation at 4 different temperatures. The results showed that neomycin interacts with BSA via Van der Waals interactions and hydrogen bonds and increase of KD with temperature rising indicated that the binding process was entropy driven. Molecular docking study confirmed that hydrogen bond was the major intermolecular force stabilizing neomycin-BSA complex. Conclusion: The attained results showed that neomycin molecules can efficiently distribute within the body after interaction with BSA in spite of having hydrophilic properties. Besides, SPR can be considered as a useful instrument for study of the interaction of hydrophilic drugs with SA.

Molecular Dynamics Simulation Study of the HIV-1 Protease Inhibit ion Using Fullerene and New Fullerene Derivatives of Carbon Nanostructures.

BACKGROUND: The water insolubility of fullerene C60 nanostructure greatly hampers its biological applications as an effective HIV-1 protease inhibitor, which suggests to synthesis new C60 derivatives with different functional polar groups. METHOD: The new carbon nanostructures of fulleropyrrolidines with one and two polar acetoxyhydroxyl (AcH) groups (C60-A and C60-B, respectively) were constructed to evaluate their interactions and binding affinity into HIV-1 protease active site via theoretical molecular docking and molecular dynamic simulations. Data obviously indicated the higher affinity of fulleropyrrolidines derivatives C60-A and C60-B compared to fullerene C60 in interacting with HIV-1 protease active site cavity. The functional groups in C60 caused better residing of C60 derivatives in the center of active site by changing the spherical shape of C60, constructing different stable H-bonds with supporting the main π interactions between C60 and aromatic Phe53/Arg8 in protease active site. Our finding showed that the functionalization of C60 is essential for both increasing solubility and improving different π interactions of C60 with protease. Also, H-bond forming with AcH functional groups and enzyme active site residues is more important to support the van der Waals interactions between C60 fragment of fulleropyrrolidines and enzyme cavity. Since enzyme possesses aspartic acid residues in active site, C60-B with two AcH groups interacted with the active site more efficiently via additional H-bond relative to C60-A. RESULTS: Finally, the results indicate a possible use of the investigated fulleropyrrolidines derivatives as new HIV-1 protease inhibitors.