Evaluation of suppressor behavior of guanidine-derived metformin and galegine as novel potential drugs for cancer treatment: an in silico study.

There are some natural products from plants that can prevent and treat disease. Metformin, a derivative of galegine, is the basic drug to treat diabetes. Moreover, this molecule has anticancer properties that inhibit cancer cell growth and proliferation. In this study, the main interactions of galegine and metformin with various cancer-involved proteins, including mitochondrial alpha-glycerophosphate dehydrogenase, yeast NADH dehydrogenase, and transforming growth factor-ß1, were surveyed by molecular docking and molecular dynamics simulations. The results showed that each of the proteins makes complexes with the ligands via favorable non-bonded interactions, especially hydrogen bond interactions. There is greater stability for complexes containing galegine based on the root mean square deviation results. The higher structure compactness is also found in galegine receptors than in metformin receptors. Calculation of ΔGbinding, using the MM/PBSA methodology, shows that the binding energy values for metformin and galegine in interaction with each of the receptors are almost the same, and galegine has similar binding properties with metformin in interaction with the studied protein receptors. Therefore, galegine, a natural ingredient with better binding properties to cancer-involved proteins than metformin (with various side effects), can be applied as a new drug for cancer treatment.

Preparation of cerium-curcumin and cerium-quercetin complexes and their LEDs irradiation assisted anticancer effects on MDA-MB-231 and A375 cancer cell lines.

Cancer remains common and often is difficult to eradicate. In particular resistant forms like triple negative breast cancer and melanoma generally allow for very short survival. Curcumin and quercetin as two important polyphenols from plants which have different biological roles, potentially including anti-cancer effect. But their clinical application is limited due to poor solubility in aqueous medium. Photodynamic therapy (PDT) is a cancer treatment using select chemical compounds as photosensitizers, which when activated by light create toxic singlet oxygen. Studies done on plant based photosensitizers such as curcumin and quercetin have shown the ability to ablate tumors. Here we discuss using them as improved PS by making their complex with cerium ions as a delivery system for MDA-MB-231 and A375 cancer cell lines treatment. For this purpose, the MDA-MB-231 human breast cancer cell line exposed to red light irradiation (as pretreatment) then treated with curcumin and quercetin alone and also their complex with cerium. In another study the cells treated with curcumin-cerium and quercetin-cerium complex and then irradiated with blue light (photodynamic treatment). Cell survival and apoptosis were determined using MTT and fluorescence microscopy. The result showed that curcumin and quercetin in complex with cerium ions have better toxic effect against both breast and melanoma cancer cells as compared to each compound alone. The finding revealed that curcumin and quercetin in cerium complex could be considered as a new approach in the photodynamic treatment of breast and melanoma cancer cells.

Experimental investigation and molecular dynamics simulation of the binding of ellagic acid to bovine liver catalase: Activation study and interaction mechanism.

Ellagic acid (ELA), as a polyphenolic natural compound and food additive, which has reported to possess anti-carcinogenic, antioxidant, antidepressant, ameliorative and anti-mutagenic effects. In the current work, the effects of ELA on the conformation and catalytic activity of catalase were investigated by using spectroscopic techniques including ultraviolet visible (UV-vis), fluorescence, synchronous fluorescence and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy as well as molecular dynamics (MD) simulation. Kinetic studies showed that the enzymatic activity of catalase increases in the presence of ELA (almost 2-fold higher than free enzyme activity). Moreover, analysis of fluorescence data revealed two binding sites for ELA on the catalase and static type of quenching mechanism. The binding constants between ELA and catalase were obtained to be 47.35 × 107 M-1 (at 298 K) and 17.60 × 107 M-1 (at 310 K) and the binding distance was calculated to be 2.83 nm. Thermodynamic data showed that hydrogen bonds have a main role in the ELA-catalase complex formation. The best binding sites for ELA were, in the middle of ß-barrel and wrapping domain and in the middle of ß-barrel and helical domain, according to molecular docking data. MD simulation results were confirmed that ELA can increase catalase activity through increasing the distance between an upper side α-helix structure and a down side random coil structure.

Comparative study of photodynamic activity of methylene blue in the presence of salicylic acid and curcumin phenolic compounds on human breast cancer.

Curcumin and salicylic acid are both phenolic compounds and they can both affect cancer treatment efficacy. In this study, the effects of methylene blue-curcumin (CU-MB) and methylene blue-salicylic acid (SA-MB) ion pair complexes on MDA-MB-231 human breast cancer cells are studied. According to the thermodynamic parameters, the stability of curcumin and salicylic acid complexes ion pair complexes was compared. The free energy of ion pair interactions was calculated based on binding constants. A comparison of the free energies of the complexes (CU-MB: ∆G°b1 = - 21.11 kJ/mol and ∆G°b2 = - 8.37 kJ/mol, SA-MB: ∆G°b1 = - 12.92 kJ/mol and ∆G°b2 = - 9.02 kJ/mol) indicates that the interaction of methylene blue in first binding interaction with curcumin is greater than that of methylene blue with salicylic acid. Electrostatic interactions are the main forces in the binding of both compounds to methylene blue. All forces are inter-molecular physical interactions. The results of cellular experiments show that ion pairing has enhanced the reduction of cell viability. By increasing molecular stability and prevention of dimerization of methylene blue, the cell killing potential of methylene blue increases and it subsequently causes enhancement of photodynamic efficacy.

Graphene oxide-methylene blue nanocomposite in photodynamic therapy of human breast cancer.

The interaction of methylene blue (MB) as a photosensitizer with graphene oxide nano-sheets (GO) was examined in aqueous solution using UV-vis spectrophotometric techniques. MB-GO composites were prepared by mixing the solutions of GO nano-sheets and methylene blue due to interacting of the cationic methylene blue photosensitizer via electrostatic and π-π stacking or hydrophobic cooperative interactions. The cell killing potential of nanocomposite was examined on the MDA-MB-231 breast cancer cells in the absence and presence of red LED irradiation. The results demonstrated that the MB-GO nanocomposite has good performance in photodynamic therapy (PDT) during red LED irradiation. The cytotoxicity of nanocomposite caused reducing cell viability up to 20%. These effects would be due to the nano size structure of composite that could lead to effective cellular penetration. Also the significant difference has seen in lower concentrations of MB and MB-GO nanocomposite. The results show more than 40% increases in cell killing potential in lower concentrations of nanocomposite by using 2.5 µg/mL of each compound. The ratio of GO/MB can affect the interaction and higher ratios of graphene oxide (GO/MB > 1) can induce dimerization of MB. In lower concentrations and ratios of (GO/MB < 1) the free MB concentration increases and the electron shuttling effect of GO in photo activity decreases - which could affect the photocatalytic yield in PDT. The cell viability measurements confirm these effects on cancer cell killing potential of nanocomposite. According to microscopic and PDT assay results, the nanocomposite distribution and diffusion in cells enhanced the photochemical reaction yield in photodynamic therapy of MDA-MB-231 breast cancer cell line.

Interaction of insulin with colloidal ZnS quantum dots functionalized by various surface capping agents.

Interaction of quantum dots (QDs) and proteins strongly influenced by the surface characteristics of the QDs at the protein-QD interface. For a precise control of these surface-related interactions, it is necessary to improve our understanding in this field. In this regard, in the present work, the interaction between the insulin and differently functionalized ZnS quantum dots (QDs) were studied. The ZnS QDs were functionalized with various functional groups of hydroxyl (OH), carboxyl (COOH), amine (NH2), and amino acid (COOH and NH2). The effect of surface hydrophobicity was also studied by changing the alkyl-chain lengths of mercaptocarboxylic acid capping agents. The interaction between insulin and the ZnS QDs were investigated by fluorescence quenching, synchronous fluorescence, circular dichroism (CD), and thermal aggregation techniques. The results reveal that among the studied QDs, mercaptosuccinic acid functionalized QDs has the strongest interaction (∆G°=-51.50kJ/mol at 310K) with insulin, mercaptoethanol functionalized QDs destabilize insulin by increasing the beta-sheet contents, and only cysteine functionalized QDs improves the insulin stability by increasing the alpha-helix contents of the protein, and. Our results also indicate that by increasing the alkyl-chain length of capping agents, due to an increase in hydrophobicity of the QDs surface, the beta-sheet contents of insulin increase which results in the enhancement of insulin instability.

Antichaperone activity and heme degradation effect of methyl tert-butyl ether (MTBE) on normal and diabetic hemoglobins.

Because of the extensive use of methyl tert-butyl ether (MTBE) as an additive to increase the octane quality of gasoline, the environmental pollution by this compound has increased in recent decades. Environmental release of MTBE may lead to its entry to the blood stream through inhalation or drinking of contaminated water, and its interactions with biological molecules such as proteins. The present study was proposed to comparatively investigate the interactions of MTBE with hemoglobin (Hb) from diabetic and nondiabetic individuals using various spectroscopic methods including UV-visible, fluorescence, chemiluminescence, and circular dichroism. These results demonstrated the effects of MTBE on heme degradation of Hb and the reaction of these degradation products with water generating reactive oxygen species. Interaction of Hb with MTBE enhanced its aggregation rate and decreased lag time, indicating the antichaperone activity of MTBE upon interaction with Hb. Furthermore, the diabetic Hb showed more severe effects of MTBE, including heme degradation, reactive oxygen species production, unfolding, and antichaperone behavior than the nondiabetic Hb. The results from molecular docking suggested that the special interaction site of MTBE in the vicinity of Hb heme group is responsible for heme degradation.

Affinity enhancement of nanobody binding to EGFR: in silico site-directed mutagenesis and molecular dynamics simulation approaches.

Epidermal growth factor receptor (EGFR), a transmembrane glycoprotein, is overexpressed in many cancers such as head-neck, breast, prostate, and skin cancers for this reason it is a good target in cancer therapy and diagnosis. In nanobody-based cancer diagnosis and treatment, nanobodies with high affinity toward receptor (e.g. EGFR) results in effective treatment or diagnosis of cancer. In this regard, the main aim of this study is to develop a method based on molecular dynamic (MD) simulations for designing of 7D12 based nanobody with high affinity compared with wild-type nanobody. By surveying electrostatic and desolvation interactions between different residues of 7D12 and EGFR, the critical residues of 7D12 that play the main role in the binding of 7D12 to EGFR were elucidated and based on these residues, five logical variants were designed. Following the 50 ns MD simulations, pull and umbrella sampling simulation were performed for 7D12 and all its variants in complex with EGFR. Binding free energy of 7D12 (and all its variants) with EGFR was obtained by weighted histogram analysis method. According to binding free energy results, GLY101 to GLU mutation showed the highest binding affinity but this variant is unstable after 50 ns MD simulations. ALA100 to GLU mutation shows suitable binding enhancement with acceptable structural stability. Suitable position and orientation of GLU in residue 100 of 7D12 against related amino acids of EGFR formed some extra hydrogen and electrostatic interactions which resulted in binding enhancement.

Unfolding of insulin at the surface of ZnO quantum dots.

ZnO quantum dots (QDs) have been used in many biomedical applications such as bioimaging, cancer treatments and etc. Crystallinity, particle size, optical absorption and photoluminescence spectra of ZnO QDs were analyzed by X-ray diffraction (XRD), transmission electron microscopy (TEM), UV-vis absorption spectroscopy and fluorescence spectroscopy respectively. Interaction of ZnO QDs with insulin was investigated by fluorescence quenching, circular dichroism (CD), isothermal titration calorimetry (ITC) and thermal aggregation tests. The fluorescence quenching results showed a static type quenching along with red shift in synchronize fluorescence (a sign of protein unfolding). CD spectroscopy results also confirmed this unfolding and show a reduction in alpha helices content of insulin in contact with ZnO QDs and their conversion to random coils. According to ITC results, the ΔG, ΔH and binding constant of this interaction are -32.35 kJ/mol, -43.21 kJ/mol and 4.69 × 10(5) M(-1), respectively. Thermal aggregation test showed fast aggregation of insulin in the presence of ZnO QDs. Therefore in biological application of ZnO QDs such as bioimaging, presence of such QDs in vicinity of insulin could unfold this protein.