Modares Journal of Biotechnology

Abstract The COVID-19 pandemic has created a global health crisis, and developing effective treatments is essential to prevent the spread of the disease and save millions of lives. One of the key proteins involved in the replication cycle of SARS-CoV-2, the virus that causes COVID-19, is the main protease enzyme, 3CL^pro. Due to its high importance, this enzyme is the subject of molecular, structural, and clinical investigations, and efforts have been made to develop drugs that can inhibit its activity. One such drug is the chemical compound N3, which has been found to have a high inhibitory effect against 3CL^pro. However, traditional medicine perspectives on this issue have been less explored. In this research, molecular docking interaction simulation and all-atom molecular dynamics (MD) simulation were conducted to study the potential inhibitory capability of generally available 21 plant-extracted compounds against the 3CL^pro enzyme. Three compounds with the highest inhibition probability were selected from the molecular docking results and subjected to 100 ns of MD simulation to investigate their stability and structural-dynamic-energetic features. Beside the complexes stability, the results from the simulation demonstrated that, all our selected three compounds induce N3 comparable structural-dynamics characteristics to 3CL^pro and, therefore, are expected to have a similar inhibitory ability against this enzyme. Compound number 5 was found to have the most favorable binding energy and was proposed as the best plant substitute for N3. The results from this research can be directly used to design experimental research for 3CLpro enzyme inhibition, saving the time-financial cost.

Abstract Nowadays, the peptides and proteins possessing anti-cancer, anti-allergic and anti-inflammatory properties are used for disease treatment. Brazzein is a sweet protein containing 54 amino acids and according to reports, it has anti-cancer properties based on sequence and structurehas sequence. In this study, the role of position 40 aspartate in the structure and function of wild brazzein protein and mutants as well as the anti-cancer properties of the peptides obtained on the TLR5 receptor were investigated. For this, several models of mutated forms were designed and constructed using Modeller.v.9.20 software. Then, the accuracy of the models and the physico-chemical properties of wild type (WT) and mutants of D40N, D40R and D40Deletion were evaluated using various bioinformatics servers and softwares including ProtParam, ProtScale, SAVES, PIC, ModEval, and PredyFlexy. For predicting anticancer properties, the sequence of WT protein and mutants was examined and compared using ACPred and iACP servers. The quality and analysis of WT protein and mutants binding as a ligand with TLR5 receptor, triggering an anti-cancer signaling pathway, were investigated through molecular docking using HADDOCK software.The results of bioinformatics parameters analysis indicated the possibility of improving the stability of brazzein structure and function, and the probability of increasing the available surface to bind to the receptor. Moreover, based on the results of molecular docking analyses, the ability binding TLR5 receptor was higher in D40R than the other proteins indicating an increased probability in anti-cancer properties of the mutant.

Abstract Vitamins D and E are two common medicines for diabetes treatment. Among the main issues in this field is the release of insulin into the circulatory system. Increasing the stability of insulin hexamer is an evolving strategy in improving insulin secretion efficiency. Insulin protein is commonly found in three forms: monomer, dimer, and hexamer. In this study, for the first time, computational approaches were used to investigate the effect of vitamins D3 and E on the stability of insulin hexamer. The molecular docking results indicate six specific binding sites for these vitamins. These bind to the hydrophobic sites of insulin subunits due to their structural rings and hydrophobic properties. The G-mmpbsa analysis indicates the stabilizing role of both vitamins. The binding of these vitamins to the hexamer has significantly increased the binding energy between insulin subunits. Also, the number of hydrogen bonds between monomeric subunits of each insulin homodimer increased in the presence of the vitamins. It also significantly increases the number of internal hydrogen bonds of hexamer protein. Accordingly, vitamins D3 and E bind to and stabilize the insulin hexamer, resulting in a slower and more balanced insulin release as well as a longer half-life for the dimer in the bloodstream. These findings will pave the way to design a new strategy to regulate insulin release and increase its half-life in the blood for type II diabetes treatment. Besides, hexamer stabilization can be an effective treatment strategy for type I diabetes through slow release from an implanted biosensor system.

Abstract In the present study, the structure of three common anticancer drugs including 6-thioguanine (6-TG), hydroxyurea (NH) and busulfan were optimized using quantum computational and obtained minimum energy for them. Also, optimization structure of gold nanoparticle was investigated by density functional theory (DFT). Finally, the binding energy of Au nanoparticle was calculated with the optimized structures of drugs. All different sites of drugs that can be interacted with nanoparticle were considered and the most stable structure was chosen for further study. These calculations were performed using FHI-aims which is a software package based on DFT. The bond length and the best interaction energy were reported in this work. To better investigation of the location of the interaction, the type of orbitals involved in the interaction and their shapes are shown. Gap energy analysis showed that the lowest energy was related to the complex of gold nanoparticle with 6-thioguanine, which confirms the chemical stability of this drug with nanoparticle. Investigations showed that the binding energy of gold nanoparticle with drugs is busulfan > hydroxyurea> 6-thioguanine so busulfan has more affinity to bind with gold nanoparticle.
Au nanoparticle as an anticancer drug deliver was studied with the molecular docking calculations. The human albumin serum (HSA) binding with three anticancer drugs was docked individually with Hex 8 software and their active sites of interaction were shown as well as. Finally, the binding energies and types of interactions such as electrostatic, van der Waals and hydrogen bonds between HSA and Au@ drugs were presented, clearly.

Abstract 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.

Abstract Marine organisms are one of the valuable resource of pharmaceutical. In the last decade, the commercial value of these organisms and the use of compounds derived from them in biological research and drug development, have made them as an important new source for anti-cancer drugs. Microtubules are one of important drug targets in cancer cells therapy and their related inhibitors are being developed widely. In this study the structure of more than 3,000 compounds that contributed marine organism were constructed and optimized by ChemAxon. The affinity of compounds into colchicine/epothilone binding sites in αβ-tubulin structure, was examined using structure-based virtual screening (docking). Results of docking studies were shown that some compounds have high and better binding affinity than colchicine and epothilone inhibitors. MNP14107 and MNP0565 compounds have high affinity for the colchicine and epothilone binding sites respectively. We propose the MNP14107 and MNP0565 compounds as new and the best candidates for the inhibition of tubulin.