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Regarding the importance of inhibiting VEGF and unique features of VHHs as a new generation of antibody-based therapeutics, the present study aimed to generate VHHs against the receptor binding domain of VEGF, thereby blocking of VEGF binding to its receptor. After preparing the gene repertoire of VHH fragments from an immunized camel, a VHH phage display library was constructed. We adopted a stringent successive biopanning to isolate the phages displaying VHH with high affinity to VEGF-RBD.A significant enrichment of phages that specifically bound to the target protein was obtained after six rounds of panning. Of the specific clones with high binding affinity screened by monoclonal phage ELISA, 52% shared the same VHH sequence, showing its high enrichment. Using molecular simulation of antigen-antibody interaction based on the crystallographic information of VEGF/VEGFR2, molecular dynamics simulations and MM/PBSA free energy calculations, we provide a reliable picture of the binding site of antibody on antigen. The key residues in the VEvhh1-VEGF interface were dissected and the energetics was analyzed by MM/PBSA. The results of studies revealed that VEvhh1 binds to the receptor binding site of VEGF with high binding energy and showed the highest affinity to the residues of VEGF which are responsible for VEGF binding to VEGFR2. Also the antibody potently covers these key functional residues of VEGF, thereby inhibiting VEGF binding to its receptor and probably abrogating its biological activity. This study may represent VEvhh1 as an anti-VEGF and anti-angiogenic candidate.

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Aims: The Mesd is a universal inhibitor and has therapeutic effect against triple negative breast cancer. The peptide derived from carboxyl terminal, similar to protein, acts as an inhibitor of the pathway. The aim of this study was to investigate the probable binding sites of Mesd and its peptide derived from carboxyl terminal on LRP6 first and second beta-propeller domains from a structural point of view in drug design.
Materials & Methods: This experimental study was conducted, using blind and site-directed molecular docking simulation with ClusPro and Haddock and molecular dynamic simulation. The binding sites of Mesd and the peptide on the first and second beta-propeller domains of receptor LRP6 were investigated and the selected complexes were structurally analyzed.
Findings: Extensive levels of Mesd protein were found to interact with LRP6 and the levels involved in the peptide were much lower. The binding region of Mesd to LRP6 was from the carboxyl terminal. The binding region of the peptide and the protein on LRP6 was a similar region between First and Second Beta-Propeller Domains of LRP6. The RMSD and RMSF chart of the Mesd complex and its peptide was approximately the same with the first functional domain of the LRP6 co-receptor.
Conclusion: The binding region of the peptide and the protein on LRP6 is not completely similar, but according to molecular simulation of selected complexes, the pattern of the inhibition mechanism is common and emphasizes on inter domain motion control from a structural point of view. Interactive region of each ligand is similar to a region of the co-receptor, which has maximum flexibility. Molecular docking simulation of Mesd and co-receptor shows important role of carboxyl terminal of the protein to bind to LRP6.

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The interactions between carbon nanotubes (CNTs) and proteins were considered much attention. Advanced CNT applied biomolecules require mutual understanding of their interactions with biological molecules. Enhanced biomedical applications of CNTs have necessitated the need for the understanding their interaction with biomolecules. Non-covalent interactions of blood peptides, such as hepcidin, with carbon nanotubes, have important effects in a wide range of biological applications that are detected by analyzing the thermodynamic parameters of the interaction between CNTs and peptides. In addition, the effects of different parameters in order to evaluate how the interaction of CNTs with peptide affects and structural changes and stability of peptides were studied. In this study, based on molecular dynamics (MD) simulation, the structural changes of hepcidin 20 in interaction with multi walled carbon nanotubes (MWCNTs-COOH ) were investigated. The simulation results revealed that carbon nanotubes cause to loose the hepcidin structure and make structural changes in this peptide. On the other hand, the loose of the hepcidin structure may lead to a change in its activity. The results indicated that significant changes were made in the structure of hepcidin 20 in the presence of carbon nanotubes. The difference of parameter amounts calculated in heptidine 20 is related to their N-terminal, and loop regions.  

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Integrin inhibitors may change conformational and dynamical properties of integrin, but its molecular properties in this process is not clearly understood. Tumstatin is an anti-angiogenesis protein derived from collagen XVIII, but little is known about how tumstatin applies its antiangiogenic and antitumor effects. It has been reported that 18 amino acids fragment of tumstatin has anti-tumor activities similar to tumstatin. We used molecular docking and molecular dynamic simulations to describe inhibitor activity of peptide in molecular level. We described the binding of this peptide to Hybrid/EGF-4 interface and that these interactions might contribute to improved hydrophobic interactions at these regions and also fixed the mobile domains of integrin. In the complex, we recognized a novel binding site on integrin for integrin inhibitors that may have critical role in integrin inhibition. These results support the idea that hydrophobic interactions between Hybrid/EGF-4 domain and peptide-anti tumor might contribute to stability of bended state and therefore inhibit integrin activation.  Our finding can be applied to understand the mechanism of out-in pathway integrin signaling and development of integrin targeted drug.

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Chemotherapy is one of the most effective and common treatments for cancer. Multi-drug resistance and drug side effects are one of the major obstacles to successful chemotherapy. To address these limitations and achieve better drug efficacy, nanosystem-based combination therapy offers a promising approach. This study aimed to synthesize, characterize, and investigate the synergistic effect of nanoliposomes loaded with doxorubicin and epigallocatechin-3-gallate (EGCG) on MCF-7 breast cancer cell lines. In the present study, nanoliposomes were prepared by passive loading and thin-film hydration. The characterization of nanoliposomes such as size distribution, zeta potential, the loading rate, drug release profile, and toxicity were measured. The mean diameter of nanoliposomes was 82.5 nm, their surface charge was -24.2 mV and drug loading was about 80%. The interaction of doxorubicin and EGCG with nanoliposomes was mediated by electrostatic and van der Waals bonds and EGCG has a deceasing effect on the doxorubicin release profile but the observed differences are not significant. The toxicity and viability data indicate that the simultaneous use of these two drugs increased the toxicity of the cells. Nanoliposomes containing doxorubicin were not able to reduce viability to below 50% in monotherapy with 5×10^-3 μM. While, the amount of viability dramatically reduced to below 50%, in combination with EGCG, resulting as combination chemotherapy. Consequently, the concomitant administration of EGCG with doxorubicin may be a suitable candidate for chemotherapy.

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Abstract. FZD7 receptor is considered as an emerging target for the treatment of Wnt-βcatenin related cancers. This transmembrane receptor is overexpressed in many cancer types like breast cancer and ovarian carcinoma, and so selective targeting of this receptor has a great therapeutic capacity. On the other hand, one of the mechanisms proposed for the anticancer effect of Atrial natriuretic peptide (ANP) that known as a heart hormone at first, is Wnt-βcatenin inhibition through an FZD dependent manner but, the molecular mechanism of this inhibition is not clear. Here, using computational methods including molecular docking and molecular dynamics simulation, also designing a cellular system that enabled us to trace Wnt-βcatenin kinetics directly, we investigated the mechanism of the peptide inhibitory potential against the pathway. Our computational results show that ANP can directly interact with FZD7 and also, its binding site on FZD7 overlap to the binding region of the Wnt carboxyl-terminal domain (Wnt-CTD). The finding of the silencing experiments demonstrates the dependency of Wnt-βcatenin signaling of the cellular system to FZD7. The decrease of βcatenin in cells treated to ANP and Wnt is also significant to compare to the control experiments. Finally, our results show that ANP is a potential scaffold to design selective peptide against FZD7.

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