Proposing of fungal endophyte secondary metabolites as a potential inhibitors of 2019-novel coronavirus main protease using docking and molecular dynamics.

In this study, the inhibitory potential of 99 fungal derived secondary metabolites was predicted against SARS-CoV-2 main protease by using of computational approaches. This protein plays an important role in replication and is one of the important targets to inhibit viral reproduction. Among the 99 reported compounds, the 9 of them with the highest binding energy to Mpro obtained from the molecular docking method were selected for the molecular dynamic simulations. The compounds were then investigated by using the SwissADME serve to evaluate the compounds in terms of pharmacokinetic and druglikness properties. The overall results of different analysis show that the compound RKS-1778 is potentially more effective than others and form strong complexes with viral protease. It also had better pharmacokinetic properties than other metabolites, so predicted to be a suitable candidate as anti SARS-CoV-2 bioactive.Communicated by Ramaswamy H. Sarma.

Computational assessment of lipid facilitated membrane permeation of vancomycin using force-probe molecular dynamic simulation.

In this study the efficacy of different edible lipids for drug permeation enhancement of vancomycin through biological membrane was investigated using molecular dynamic simulation. In this regard, at first the ability of the lipids for complex formation with the drug was evaluated for number of most common edible lipids including tripalmitin (TPA), trimyristin (TMY), labrafil (LAB), glycerol monostearate (GMS), glycerol monooleate (GMO), Distearoylphosphorylethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), Dipalmitoylphosphatidylcholine (DPPC), cholesterol (CL), stearic acid (SA), palmitic acid (PA) and oleic acid (OA). Then the complexes were pulled thorough a bilayer membrane while the changes in force were probed. The results showed that besides the SA, PA and OA the other examined lipids were able to perform a perfect molecular complex with the drug. Also the results of pulling simulation revealed that the least of force was needed for drug transmittance through the membrane when it was covered by LAB, TMY and DSPE. These results indicated that these lipids can be the excellent materials of choice as permeation enhancer for preparing a proper oral formulation of vancomycin.Communicated by Ramaswamy H. Sarma.

A molecular dynamics study on using of naturally occurring polymers for structural stabilization of erythropoietin at high temperature.

Today the nano drug delivery systems are among the hot topics in drug design and pharmacy studies. Extensive researches are conducted worldwide for obtaining more effective therapeutics and screen the best drug carrier in-vivo and in-vitro. Considering the high cost of such experiments and the ethical issues linked with in-vivo studies, the in-silico analysis provides the time and cost-effective opportunity to evaluation of physiochemical properties and the interactions between drugs and their carriers. In this study using molecular dynamics (MD) simulation, five commonly used biodegradable biopolymers in pharmaceutical formulations including Chitosan, Alginate, Cyclodextrin, Hyaluronic Acid, and Pectin were investigated as proper carriers for the erythropoietin (EPO) in heat stress. The EPO was simulated in different temperatures of 298 and 343 K and the ability of polymers for temperature stabilization of the protein was evaluated comparatively. Overall, the results obtained in this study suggest that the pectin polysaccharide is the preferable carrier than others in term of protein stability in high temperatures and using for the delivery of erythropoietin.Communicated by Ramaswamy H. Sarma.

In silico investigation on the inhibitory effect of fungal secondary metabolites on RNA dependent RNA polymerase of SARS-CoV-II: A docking and molecular dynamic simulation study.

The newly emerged Coronavirus Disease 2019 (COVID-19) rapidly outspread worldwide and now is one of the biggest infectious pandemics in human society. In this study, the inhibitory potential of 99 secondary metabolites obtained from endophytic fungi was investigated against the new coronavirus RNA-dependent RNA polymerase (RdRp) using computational methods. A sequence of blind and targeted molecular dockings was performed to predict the more potent compounds on the viral enzyme. In the next step, the five selected compounds were further evaluated by molecular dynamics (MD) simulation. Moreover, the pharmacokinetics of the metabolites was assessed using SwissADME server. The results of molecular docking showed that compounds 18-methoxy cytochalasin J, (22E,24R)-stigmasta-5,7,22-trien-3-ß-ol, beauvericin, dankasterone B, and pyrrocidine A had higher binding energy than others. The findings of MD and SwissADME demonstrated that two fungal metabolites, 18-methoxy cytochalasin J and pyrrocidine A had better results than others in terms of protein instability, strong complex formation, and pharmacokinetic properties. In conclusion, it is recommended to further evaluate the compounds 18-methoxy cytochalasin J and pyrrocidine A in the laboratory as good candidates for inhibiting COVID-19.

Interactions and effects of food additive dye Allura red on pepsin structure and protease activity; experimental and computational supports.

BACKGROUND AND PURPOSE: Today, color additives such as Allura red (AR) are widely used in different kinds of food products. Pepsin is a globular protein that is secreted as a digestive protease from the main cells in the stomach. Because of the important role of pepsin in protein digestion and because of its importance in digestive diseases the study of the interactions of pepsin with chemical food additives is important. EXPERIMENTAL APPROACH: In this study, the interactions between AR and pepsin were investigated by different computational and experimental approaches such as ultraviolet and fluorescence spectroscopy along with computational molecular modeling. FINDINGS/RESULTS: The experimental results of fluorescence indicated that AR can strongly quench the fluorescence of pepsin through a static quenching. Thermodynamic analysis of the binding phenomena suggests that van der Waals forces and hydrogen bonding played a major role in the complex formation. The results of synchronous fluorescence spectra and furrier transformed infra-red (FTIR) experiments showed that there are no significant structural changes in the protein conformation. Also, examined pepsin protease activity revealed that the activity of pepsin was increased upon ligand binding. In agreement with the experimental results, the computational results showed that hydrogen bonding and van der Waals interactions occurred between AR and binding sites. CONCLUSION AND IMPLICATIONS: From the pharmaceutical point of view, this interaction can help us to get a deeper understanding of the effect of this synthetic dye on food digestion.

Evaluation of the effects of isoniazid and rifampin on the structure and activity of pepsin enzyme by multi spectroscopy and molecular modeling methods.

Pepsin is an aspartic protease that is involved in the digestion of food in the stomach of mammals. Continuous and long-term use of therapeutic agents will cause chronic contact of the drug with pepsin, and as a result, the structure and function of enzyme may change. In this regard the interactions of isoniazid and rifampin as the first line treatments of tuberculosis with pepsin were investigated by various methods such as fluorescence spectroscopy, FTIR, molecular docking and molecular dynamics simulation. Based on the results obtained in this study, the mentioned drugs can form stable complexes with pepsin and the structure of protein changes slightly. According to the results, the major forces in the formation of the protein-drug complex are electrostatic and hydrophobic forces for isoniazid and rifampin respectively and isoniazid shows to form a stronger binding with protein. The FTIR spectrum of the protein shows that little change was occurred in the structure of pepsin in the presence of the drugs. Molecular modeling results of the binding of isoniazid and rifampin to the pepsin confirm laboratory results and show that the binding site of drugs is close to the active site of the enzyme. Also, the activity of pepsin in the presence of both drugs has significantly increased.

Cholesterol-lowering drugs the simvastatin and atorvastatin change the protease activity of pepsin: An experimental and computational study.

In this study, the effect of long-term use drugs of cholesterol-lowering atorvastatin and simvastatin on the activity and molecular structure of pepsin as important gastric enzyme was investigated by various experimental and computational methods. Based on the results obtained from fluorescence experiments, both drugs can bond to pepsin and quench the fluorescence intensity of protein through the static quenching mechanism. Also analysis of the thermodynamic parameters of binding the drugs to pepsin showed that the main forces in the complex formation for both are hydrophobic interactions and van der Waals forces. The effects of the drugs on the enzymatic activity of pepsin were then investigated and results showed that in the presence of both drugs the catalytic activity of the enzyme was significantly increased in lower (0.3-0.6 mM) concentrations however about the atorvastatin, increasing the concentration (0.9 mM) decreased the protease activity of pepsin. Also as a result of the FTIR studies, it was found that binding of the drugs to protein did not significant alteration in the structure of the protein. In order to obtain the atomic details of drug-protein interactions, the computational calculations were performed. The results in good agreement with those obtained from the experimental for interaction; confirm that the drugs both are bind to a cleft near the active site of the protein without any change in the structure of pepsin. Overall from the results obtained in this study, it can be concluded that both simvastatin and atorvastatin can strongly bond to a location close to the active site of pepsin and the binding change the enzymatic activity of protein.

A study on the protease activity and structure of pepsin in the presence of atenolol and diltiazem.

Pepsin, as the main protease of the stomach, plays an important role in the digestion of food proteins into smaller peptides and performs about 20% of the digestive function. The role of pepsin in the development of gastrointestinal ulcers has also been studied for many years. Edible drugs that enter the body through the gastrointestinal tract will interact with this enzyme as one of the first targets. Continuous and long-term usage of some drugs will cause chronic contact of the drug with this protein, and as a result, the structure and function of pepsin may be affected. Therefore, the possible effect of atenolol and diltiazem on the structure and activity of pepsin was studied. The interaction of drugs with pepsin was evaluated using various experimental methods including UV-Visible spectroscopy, fluorescence spectroscopy, FTIR and enzymatic activity along with computational approaches. It was showed that after binding of atenolol and diltiazem to pepsin, the inherent fluorescence of the protein is quenched. Determination of the thermodynamic parameters of interactions between atenolol and diltiazem with pepsin indicates that the major forces in the formation of the protein-drug complexes are hydrophobic forces and also atenolol has a stronger protein bonding than diltiazem. Additional tests also show that the protease activity of pepsin, decreases and increases in the presence of atenolol and diltiazem, respectively. Investigation of the FTIR spectrum of the protein in the presence and absence of atenolol and diltiazem show that in the presence of atenolol the structure of protein has slightly changed. Molecular modeling studies, in agreement with the experimental results, confirm the binding of atenolol and diltiazem to the enzyme pepsin and show that the drugs are bind close to the active site of the enzyme. Finally, from experimental and computational results, it can be concluded that atenolol and diltiazem interact with the pepsin and change its structure and protease activity.

Multi spectroscopy and molecular modeling aspects related to drug interaction of aspirin and warfarin with pepsin; structural change and protease activity.

This study evaluates the biochemical interactions between two widely used anticoagulants agents, Aspirin and Warfarin, with the Pepsin as the main stomach protease. These two drugs usually prescribe orally for long period daily use to reduce cardiovascular and thrombi death which leads to being in close contact with Pepsin. This interaction could induce related gastrointestinal problems such as peptic ulcer. In this regard, the conformational changes and enzymatic activity of the Pepsin induced by Aspirin and Warfarin were studied by using several spectroscopic methods along with molecular modeling approaches. Results confirm the formation of stable complexes between protein and drugs which leads to slight subsequent conformational changes of protein structure. The quenching mechanisms for both drug-Pepsin interactions are static. In the case of Warfarin, the hydrophobic interactions are the most important interactions. Also for Aspirin, hydrogen bond and van der Waals forces are mainly involved in the binding process. The Warfarin shows the induction of some conformational changes resulted in suppressing the protease activity and the Aspirin reversely enhanced the enzyme activity function. This study provides useful information regarding the effects of Warfarin and Aspirin on Pepsin which are helpful for the choosing of therapeutics depending on the patients' condition.

An innovative green sensing strategy based on Cu-doped Tragacanth/Chitosan nano carbon dots for Isoniazid detection.

Although Isoniazid (INH) is one of the drugs used as the first line treatment of tuberculosis, its high concentrations in the human body can cause severe complications such as; recurrent seizures, profound metabolic acidosis, coma and even death. Hence it is necessary to designing the sensors capable of detecting very low amounts of drug. A Cu doped Tragacanth/Chitosan carbon dot (CD) with excellent optical properties and photo-thermal stability was synthesized, characterized and used for sensing Isoniazid by a fluorescence Off-ON mechanism based on redox reaction between INH and Fe3+ as quencher. During the first step of reaction, Fe3+ bind to the CDs and due to an electron transfer process the fluorescence intensity of CDs is quenched. There after by introduction of Isoniazid to the CDs-Fe3+ system, Fe3+ converts to Fe2+ and the fluorescence was recovered. Experiments confirm that new method has high ability to detect low concentration of Isoniazid even in the presence of other drugs and interfering materials. In conclusion, this innovative strategy for developing a low cost and sensitive sensor can be used in future health-related programs.

TSGA10 overexpression inhibits angiogenesis of HUVECs: A HIF-2α biased perspective.

Testis-specific gene antigen 10 (TSGA10) is a protein overexpressed in most cancers; except for some certain types where its expression is reduced. TSGA10 overexpression in HeLa cells has been shown to disrupt hypoxia inducible factor-1α (HIF-1α) axis and exert potent inhibitory effects. Since HIF-1α is structurally and biochemically similar to HIF-2α, TSGA10 is expected to bind HIF-2α and inhibit its function as well. This study elucidated that increased expression of TSGA10 in manipulated human umbilical vein endothelial cells (HUVECs) decreased the proliferation and migration of these cells as affirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and wound healing tests, respectively. It also inhibited in vitro angiogenesis of these cells in 3D collagen-cytodex model. Expression levels of genes controlled by HIF-2α including autocrine vascular endothelial growth factor (VEGF) were also assessed using real-time PCR. Our bioinformatic analysis also showed that TSGA10 could bind HIF-2α. Moreover, flow cytometry results indicated a cell cycle arrest in G2/M. Therefore, this study showed that overexpression of TSGA10, as a tumor suppressor gene, in endothelial cells resulted in decreased proliferation, migration and therefore, angiogenic activity of HUVECs. Since angiogenesis is vital for tumor development and metastasis, our findings could be of clinical significance in cancer therapy.