In-silico study MM/GBSA binding free energy and molecular dynamics simulation of some designed remdesivir derivatives as the inhibitory potential of SARS-CoV-2 main protease.

Background and purpose: Coronavirus disease (COVID-19) is one of the greatest challenges of the twentieth century. Recently, in silico tools help to predict new inhibitors of SARS-CoV-2. In this study, the new compounds based on the remdesivir structure (12 compounds) were designed. Experimental approach: The main interactions of remdesivir and designed compounds were investigated in the 3CLpro active site. The binding free energy of compounds by the MM-GBSA method was calculated and the best compound (compound 12 with the value of -88.173 kcal/mol) was introduced to the molecular dynamics simulation study. Findings/Results: The simulation results were compared with the results of protein simulation without the presence of an inhibitor and in the presence of remdesivir. Additionally, the RMSD results for the protein backbone showed that compound 12 in the second 50 nanoseconds has less fluctuation than the protein alone and in the presence of remdesivir, which indicates the stability of the compound in the active site of the Mpro protein. Furthermore, protein compactness was investigated in the absence of compounds and the presence of compound 12 and remdesivir. The Rg diagram shows a fluctuation of approximately 0.05 A, which indicates the compressibility of the protein in the presence and absence of compounds. The results of the RMSF plot also show the stability of essential amino acids during protein binding. Conclusion and implications: Supported by the theoretical results, compound 12 could have the potential to inhibit the 3CLpro enzyme, which requires further in vitro studies and enzyme inhibition must also be confirmed at protein levels.

Effect of chamomile aromatherapy with and without oxygen on pain of women in post cesarean section with spinal anesthesia: A randomized clinical trial.

Background: Pain is the most common side effect in cesarean section with spinal anesthesia. It seems that oxygen therapy and chamomile aromatherapy may diminish pain. The present study was conducted to examine and compare the effect of chamomile aromatherapy with and without oxygen on the severity of pain of women following cesarean section surgery with spinal anesthesia. Methods: The present randomized clinical trial study was carried out on 136 women undergoing cesarean section surgery with spinal anesthesia at Imam Sajad Hospital, Yasuj, Iran in 2020. The eligible women were assigned into four 34-member groups including oxygen therapy plus aromatherapy, oxygen therapy, aromatherapy, and control via block randomization. Each of these interventions were performed 6, 6.30 and 7 h post operation. In the first intervention group, one drop of chamomile essential oil with distilled water was poured into a small nebulizer using a simple mask connected to 6 L of oxygen. The second intervention group received oxygen without chamomile aromatherapy at similar times, and the third intervention group received chamomile aromatherapy without oxygen. The control group received only routine interventions. The instrument used in the research was visual analog scale which was completed by the researcher 6, 12, 18 h after cesarean section. The data were analyzed by the SPSS software version 20. Results: There was a significant difference in the intensity of pain of patients between the various groups of study following the interventions (P < 0.001). Pain intensity reduced significantly in the group receiving combined intervention of chamomile aromatherapy plus oxygen compared to the other three groups. Moreover, the pain intensity diminished more in the groups undergoing each of these interventions alone as compared to the control group (P < 0.05). Conclusions: The combined intervention of chamomile aromatherapy with oxygen was more effective than each of the chamomile aromatherapy and oxygen interventions alone in reducing the pain of cesarean section patients though each intervention alone was still effective in lowering pain post-operation.

Empagliflozin Exhibits Hepatoprotective Effects Against Bile Duct Ligation-induced Liver Injury in Rats: A Combined Molecular Docking Approach to In Vivo Studies.

BACKGROUND: Cholestatic liver damage is a chronic disease caused by dysfunction of the hepaticbiliary system. Oxidative stress and inflammation are essential factors in the pathogenesis of cholestasis. Thus, the current study was designed to examine the effect of empagliflozin on bile duct ligation-induced liver damage in rats. METHODS: This study was done on male Wistar rats, which were randomly assigned to the four experimental groups: sham control (SC), bile duct ligation (BDL), SC plus empagliflozin (SC+EMPA) (receiving 10 mg of EMPA orally for 7 days), BDL plus empagliflozin 10 mg/kg (BDL+ EMPA). At the end of the study, the rats were sacrificed, and serum and tissue samples were collected to analyze biochemical parameters, biomarkers of oxidative stress, inflammatory markers, and histopathological changes. The molecular docking technique was performed to elucidate the interaction of EMPA and Cu/Zn-superoxide dismutase (SOD1). RESULTS: The results showed that BDL elevated the serum activity of ALT, AST, ALP, and levels of TBIL and TPro. BDL also intensifies the oxidative stress state in rats, which was confirmed by augmenting lipid peroxidation (MDA), protein oxidation (PCO), and altering antioxidant defense parameters through decreased SOD, catalase (CAT), and glutathione peroxidase (GPX) levels. Furthermore, the histopathological changes in the liver demonstrated the aggravation of inflammation and oxidative stress. In contrast, treatment with EMPA has shown anti-inflammatory and anti-oxidant effects by reducing TNF-α and IL-6 pro-inflammatory marker proteins, restoring the antioxidant status (increased SOD and GPX), reducing ALT, AST, ALP, TBIL levels, and protein oxidation, and improving the histopathological alterations through reducing bile duct proliferation, fibrosis, focal and portal inflammation. According to the attained findings, the SOD1 activity can be regulated by the EMPA. Our documentation presents direct evidence at the molecular level related to the ability of EMPA to exert its antioxidant performance through certain measures in a particular molecular route. CONCLUSION: The results showed EMPA to have hepatic protective effects in rats against cholestatic liver injury, an effect mediated by its antioxidant and anti-inflammatory properties.

Anti-Helicobacter pylori Compounds from Oliveria decumbens Vent. through Urease Inhibitory In-vitro and In-silico Studies.

Oliveria decumbens Vent. has been used by indigenous people of southwest Iran for treating peptic ulcers and gastrointestinal infections. This study aimed to investigate the antibacterial activity of Oliveria decumbens extract and fractions and to analyze the bioactive components of the fractions. Total plant extract and different fractions of Oliveria decumbens Vent. were prepared. Antibacterial activities were evaluated against the clinical strain of Helicobacter pylori and standard strains of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa using agar dilution and disc diffusion methods. Phytochemical analysis of the fractions was performed using silica gel chromatography and 1D and 2D NMR spectroscopy. Moreover, the urease inhibitory effects of the isolated compounds were assessed in-vitro and in-silico. Three novel kaempferol derivatives and two thymol derivatives were isolated from Oliveria decumbens aerial parts, and the structures were determined by comparison with published data. The n-hexane fraction was found to exert the most significant anti-H. pylori activity with the minimum inhibitory concentration of 50 µg/mL. All fractions demonstrated antibacterial activity toward S. aureus. In-vitro urease inhibition assay showed that stigmasterol, tiliroside, and carvacrol were found to be the most potent enzyme inhibitors in the isolated compounds. Molecular interactions of the compounds with the active site of urease were supported by the molecular docking analysis. Novel bioactive compounds in Oliveria decumbens were described in this study. The antibacterial effects suggested the potential use of the compounds in pharmaceutical formulations inconsistent with the traditional use of the plant in the treatment of gastrointestinal infections.

Portulaca oleracea methanolic extract attenuate bile duct ligation-induced acute liver injury through hepatoprotective and anti-inflammatory effects.

INTRODUCTION: Cholestasis is a liver disease caused by a malfunction of the hepato-biliary system. Oxidative stress as a systemic complication is the main characteristic of cholestasis. The aim of this study was to evaluate the anti-inflammatory and hepatoprotective effects of Portulaca oleracea (PO) methanolic extract on liver dysfunction and tissue damage induced by bile duct ligation (BDL) in rats. MATERIALS AND METHODS: Twenty-eight male Wistar rats were randomly divided into four groups: sham control (SC), BDL alone, SC plus 500 mg/kg methanolic extract of PO orally for 1 week, and BDL plus 500 mg/kg methanolic extract of PO orally for 1 week. After 1 week, the animals were anesthetized, and the liver and blood samples were taken from each animal. Biochemical parameters, oxidative stress biomarkers, histopathological changes, as well as the gene expression of IL-1, TNF-α, TGF-ß, and α-SMA have been evaluated. RESULTS: The methanolic extract of PO at a dose of 500 mg/kg significantly decreased the plasma levels of aminotransferases, alkaline phosphatase as compared to BDL group (P < 0.05), while it had no significant effect on the levels of oxidative stress markers in the hepatic tissue. The plasma level of malondialdehyde and ferric-reducing antioxidant power were markedly elevated in the BDL group in comparison to SC group (P < 0.05), while treatment with PO significantly reduced these markers (P < 0.05). The administration of PO attenuated hydroxyproline content, bile duct proliferation, and inflammation score in the cholestatic liver in contrast to non-treated BDL rats (P < 0.05). Moreover, the methanolic extract of PO markedly declined the expression of TNF-α and TGF-ß pro inflammatory genes in contrast to BDL rats. CONCLUSIONS: Taken together, our findings showed that PO attenuated liver injury by decreasing liver function tests, inflammation, and hydroxyproline content. As a result, it is suggested that PO can be applied in cholestatic liver damage as a therapeutic or adjuvant agent.

Protective Effects of Hydroalcoholic Extract of Rosa canina Fruit on Vancomycin-Induced Nephrotoxicity in Rats.

Vancomycin-induced nephrotoxicity (VIN) has been reported to occur in 5-35% of recipient patients. The aims of the study were to evaluate protective effects of Rosa canina (RC) on VIN in rats. Rats were randomly divided into five groups as follows: control group I, group II (received VAN 400 mg/kg/day, every 12 h at doses of 200 mg/kg/day, for 7 consecutive days), group III (VAN + RC 250 mg/kg/day, for 7 consecutive days), group IV (VAN + RC 500 mg/kg/day, for consecutive days), and group V (received RC 500 mg/kg/day, for consecutive 7 days). On the eighth day after anesthetizing the animals, blood samples were taken from the heart, and then, the kidneys were removed to investigate kidney function, oxidative stress, and histopathological marker. Also, the chemical composition of RC extract was identified by GC-MS analysis. Oral dose of 500 mg/kg RC extract significantly reduced the serum levels of blood urea nitrogen (BUN), creatinine (Cr), malondialdehyde (MDA), and nitric oxide (NO) and also the kidney tissue MDA, protein carbonyl, and NO metabolites (nitrite) levels compared to the VAN-treated group (P < 0.05). Based on histopathological analysis, RC extract at the dose of 500 mg/kg inhibited the destructive effects of VAN on kidney tissues. GC-MS analysis indicated that the main compositions were found to be lactose (21.96%), 3-t-butyloxaziridine (20.91%), and 5-oxymethylfurfurole (16.75%). The results indicated that oral administration of RC was able to reduce VAN-induced nephrotoxicity in rats, possibly through antioxidant pathways.

Inactivation of the superoxide dismutase by malondialdehyde in the nonalcoholic fatty liver disease: a combined molecular docking approach to clinical studies.

The objective of the present study was to investigate the plasma levels of oxidative stress markers and the activity of antioxidant enzymes in NAFLD and healthy subjects. Furthermore, the interaction behaviors of malondialdehyde (MDA) with Cu/Zn superoxide dismutase (SOD1) enzyme were elucidated by molecular docking. The study involved 60 patients with NAFLD and 25 healthy volunteers. The plasma levels of oxidative stress parameters and antioxidant enzymes activity were determined. NAFLD patients had significantly higher alanine aminotransferase, MDA and nitric oxide metabolites values, as well as significantly lower total thiol and SOD activity than the control group. Based on the molecular docking, MDA could deactivate the enzymatic activity of SOD1. Impaired antioxidant defense systems may be involved in the progression of NAFLD. This study provides direct evidence at a molecular level to explain that MDA may exert its oxidant activity by specific action within the specific molecular pathway.HighlightsImpairing antioxidant defense systems may be a main factor in the progression of nonalcoholic fatty liver disease (NAFLD).Increasing MDA and NO metabolites, as well as decreasing TSH values and SOD activity in NAFLD patients as compared to control subjectsIncreasing MDA level in NAFLD patients may be inactivate SOD activity by reaction with the key residues Cu ion inside active site of the enzyme catalytic site.

Antioxidant and protective effect of Stachys pilifera Benth against nephrotoxicity induced by cisplatin in rats.

The aim of current study was to assess the antioxidant and renoprotective effects of Stachys pilifera Benth (S.P.B.) hydroalcoholic extract on nephrotoxicity induced with cisplatin (CP). Adult rats with bodyweight of 180-220 g were divided into five groups (n = 7) treated as follows: group 1, control; group 2, CP; group 3, pretreatment with S.P.B. before CP; group 4, posttreatment with S.P.B. after CP; and, group 5, S.P.B. extract. A single dose of CP (7 mg/kg) was intraperitoneally injected on the fifth day and hydroalcoholic extract of S.P.B. (500 mg kg-1  day-1 ) was orally administered. The levels of oxidative stress markers, biochemical tests, and histopathological staining were assayed in serum and renal tissue. Also, the chemical composition of S.P.B. extract was determined by GC-MS analysis. The main compositions of S.P.B. extract identified by GC-MS analysis, were hexadeca-2,6,10,14-tetraen-1-ol, 3,7,11,16-tetramethyl (24.77%), thymol (14.1%), and linolenic acid (13.4%). In groups treated and pretreated with S.P.B., blood urea nitrogen, creatinine, malondialdehyde, and nitric oxide metabolite in serum as well as malondialdehyde and protein carbonyl content of kidney tissues were significantly decreased in comparison to CP group; in contrast, total thiol group showed a significant increase in treated group as compared to CP group. Furthermore, histological investigation indicated that treatment with S.P.B. improved renal damages induced by CP. The current study showed that S.P.B. hydroalcoholic extract improved the biochemical parameters and kidney function as well as restored antioxidant activity in CP-induced nephrotoxicity. However, it needs more investigations to define the mechanism of S.P.B. action. PRACTICAL APPLICATIONS: In different regions of Iran, Stachys is demonstrated by 34 species, out of which 13 are endemic, one of these endemic species is Stachys pilifera Benth (S.P.B.). The oil of S.P.B. is mainly consisted of cis-chrysanthenyl acetate, cis-chrysanthenol, spathulenol, ß-caryophyllene, linalool, and terpinen-4-ol. Moreover, phytochemical studies have shown the presence of compounds such as diterpenes, phenylethanoid glycosides, saponins, terpenoides, and flavonoids in Stachys species. The aerial parts of S.P.B. are consumed as herbal tea to treat several disorders, for example, infections, asthma, and rheumatoid arthritis in Iranian folk medicine. The aim of current study was to evaluate the antioxidant and protective effects of S.P.B. hydroalcoholic extract on nephrotoxicity induced with cisplatin (CP). The current study showed that S.P.B. hydroalcoholic extract improved the biochemical parameters and kidney function as well as restored antioxidant activity in CP-induced nephrotoxicity. However, it needs more researches to define the mechanism of S.P.B. action.

Exploring the binding mechanism of saccharin and sodium saccharin to promoter of human p53 gene by theoretical and experimental methods.

In the past few decades, extensive discussions have been on the impact of artificial sweeteners on the risk of cancer. The present study aimed to evaluate the interaction of saccharin (SA) and sodium saccharin (SSA) with the promoter of the human p53 gene. The binding ability was assessed using the spectroscopic technique, molecular docking and molecular dynamics (MD) simulation methods. Free energy of binding has been calculated using Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. Fluorescence spectra of mentioned gene with concentration profiles of SA and SSA were obtained in a physiological condition. A gradual increase without any significant spectral shift in the fluorescence intensity of around 350 nm was evident, indicating the presence of an interaction between both compounds and gene. The docking results showed that both compounds were susceptible to bind to 5'-DG56DG57-3' nucleotide sequence of gene. Furthermore, the MD simulation demonstrated that the binding positions for SA and SSA were 5'-A1T3T4-3' and 5'-G44T45-3' sequences of gene, respectively. The binding of these sweeteners to gene made significant conformational changes to the DNA structure. Hydrogen and hydrophobic interactions are the major forces in complexes stability. Through the groove binding mode, the non-interactive DNA-binding nature of SSA and SA has been demonstrated by the results of spectrofluorometric and molecular modeling. This study could provide valuable insight into the binding mechanism of SA and its salt with p53 gene promoter as macromolecule at the molecular level in atomistic details. This work can contribute to the possibility of the potential hazard of carcinogenicity of this sweetener and to design and apply new and safer artificial sweeteners. AbbreviationsSASaccharinSSASodium SaccharinPp53gpromoter of human p53 geneMDMolecular dynamicsRMSDRoot-mean-square deviationRMSFRoot-mean-square fluctuationRgRadius of GyrationSASASolvent-Accessible Surface AreaADIAcceptable daily intakeMM/PBSAMolecular Mechanics/Poisson-Boltzmann Surface AreaCommunicated by Ramaswamy H. Sarma.

Extraction and Identification of Two Flavonoids in Phlomoides hyoscyamoides as an Endemic Plant of Iran: The Role of Quercetin in the Activation of the Glutathione Peroxidase, the Improvement of the Hydroxyproline and Protein Oxidation in Bile Duct-Ligated Rats.

BACKGROUND: Cholestatic liver disease, a serious chronic condition that develops progressive hepatic degeneration through free radicals. OBJECTIVE: The present study was designed to extract and identify two flavonoids in Phlomoides hyoscyamoides plant, native to Iran and evaluate the role of quercetin identified on the liver injury among bile ductligated rats. METHODS: This study was conducted on 25 male Wistar rats within three groups of sham control, mere bile duct-ligated, and bile duct-ligated with quercetin. The bile duct-ligated animals received quercetin at a dose of 50 mg/kg/day for 10 days, followed by biochemical tests, oxidative stress markers, activity of antioxidant enzymes and hematoxylin and eosin staining. Molecular docking was used to explore the interactive behavior of quercetin with glutathione peroxidase. RESULTS: According to analyses of the obtained extract, two main active ingredients of P. hyoscyamoides were rutin and quercetin. Bile duct-ligated group showed a significant liver necrosis, a clear increase in plasma and tissue oxidative stress parameters, and a decrease in glutathione peroxidase activity as compared to sham control group. Quercetin injection in bile duct-ligated rats resulted in significant decrease in hydroxyproline, protein carbonyl and histopathologic indexes and significant increase in glutathione peroxidase activity (P-value≤0.05). Based on the molecular docking, the quercetin was able to regulate the glutathione peroxidase activity. CONCLUSION: The quercetin acts as an enzyme inducer by renewing the glutathione peroxidase activity and inhibiting the oxidation of proteins and hence decreases the oxidative stress. These results could be a sign of confirming the positive role of quercetin in attenuating the liver damage and degeneration.

Ugi efficient synthesis, biological evaluation and molecular docking of coumarin-quinoline hybrids as apoptotic agents through mitochondria-related pathways.

Ugi reaction was a reliable procedure for the synthesis of new coumarin-quinoline frameworks. Excellent yields, mild reaction conditions and easily available and inexpensive starting materials are advantages of this protocol. Cytotoxic effects of fourteen products were investigated in A2780 human ovarian cancer cells. Two synthesized compounds (L11 and L12) exhibited more anti-cancer activity than other derivatives with IC50 values of 0.042 mmol/L and 0.102 mmol/L, respectively and were thus selected for further studies. Apoptosis was induced through the intrinsic pathway by activating caspase 9 and ended at the executioner pathway of caspase 3. Measurement of intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were also carried out for both of them. Further studies on a mechanism by Real Time-PCR and Western blot analysis were performed for anti-apoptotic proteins Bcl-2 and survivin both in mRNA and protein level relating to the untreated A2780 cells. The treatment of A2780 cells with compound L11 significantly (P-value ≤ 0.05) induced apoptosis by down-regulation of Bcl-2 and survivin both in mRNA and protein level via a single dose (0.042 mmol/L), as well as activation of caspase 9 and 3, loss of MMP, and high ROS. Accordingly, findings supported the first report under which the pro-apoptotic activity of compound L11 as an apoptosis-inducing agent was related to mitochondrial-mediated dysfunction signaling pathways. Molecular docking supports experimental outcomes. Evidently, coumarin-quinoline scaffolds are potentially favorable options for further assessment as influential chemotherapeutic agents for the future.

Maltase-glucoamylase inhibition potency and cytotoxicity of pyrimidine-fused compounds: An in silico and in vitro approach.

The prevalence of diabetes mellitus has been incremented in the current century and the need for novel therapeutic compounds to treat this disease has been significantly increased. One of the most promising approaches is to inhibit intestinal alpha glucosidases. Based on our previous studies, four pyrimidine-fused heterocycles (PFH) were selected as they revealed satisfactory inhibitory action against mammalian α-glucosidase. The interaction of these compounds with both active domains of human maltase-glucoamylase (MGAM) and their effect on human Caco-2 cell line were investigated. The docking assessments suggested that binding properties of these ligands were almost similar to that of acarbose by establishing hydrogen bonds especially with Tyr1251 and Arg526 in both C-terminal and N-terminal MGAM, respectively. Also, these compounds indicated a stronger affinity for C-terminal of MGAM. L2 and L4 made tightly complexes with both terminals of MGAM which in turn revealed the importance of introducing pyrimidine scaffold and its hinge compartment. The results of molecular dynamics simulation analyses confirmed the docking data and showed deep penetration of L2 and L4 into the active site of MGAM. Based on cell cytotoxicity assessments, no significant cell death induction was observed. Hence, these functional MGAM inhibitors might be considered as new potential therapeutic compounds in treatment of diabetes and its complications.

Trachyspermum ammi (L.) Sprague, superb essential oil and its major components on peptic ulcers: in vivo combined in silico studies.

BACKGROUND: Trachyspermum ammi (L.) Sprague is used for treating gastrointestinal disorders. Several studies indicated gastric antiulcer activity of T. ammi extract, yet the effect of its essential oil has not been studied on. OBJECTIVES: The present study evaluates chemical composition of T. ammi essential oil and anti-peptic ulcer effect of the essential oil as well as its three major components in ethanol induced-gastric ulcers in rats. METHODS: Primarily chemical composition of the essential oil was analyzed by gas chromatography-mass spectrometry (GC/MS). Rats received the essential oil (500, 250, 125, 62.5, 31.25 mg/kg), thymol (30, 100 mg/kg), para-cymene (100, 150 mg/kg) and gamma-terpinene (100, 150 mg/kg) using gavage tube along with ethanol 80%. Finally, dissected stomachs were assessed both macroscopically and microscopically to evaluate anti-ulcerative effect of the essential oil and the pure compounds. Moreover, molecular docking was utilized to explore the interactive behavior of the main components with active site residues of H+/K+ ATPase. RESULTS: Analysis of the essential oil indicated that para-cymene (37.18%), gamma-terpinene (35.36%) and thymol (20.51%) are the main components. Administration of different doses of the essential oil noticeably diminished the number of peptic ulcers in a dose-dependent manner. Among the main components, thymol was more potent than para-cymene and gamma-terpinene. Administration of the essential oil (500 mg/kg) and thymol (100 mg/kg) observed maximum inhibition percentage (98.58% and 79.37%, respectively). Molecular docking study provides the evidence of thymol ability to inhibit H+/K+ ATPase. CONCLUSIONS: The findings revealed that T. ammi essential oil can be applied to treat gastric ulcer as a natural agent. Graphical abstract.

Hepatoprotective and antioxidant activity of hydroalcoholic extract of Stachys pilifera. Benth on acetaminophen-induced liver toxicity in male rats.

BACKGROUND: Acetaminophen (APAP) at high doses causes adverse side effects such as hepatotoxicity. The aim of the current study was to investigate the hepatoprotective and antioxidant effects of hydroalcoholic extract of Stachys pilifera. Benth (SP) on hepatotoxicity induced by APAP in male rats. METHODS: Adult male Wistar rats were allocated into four groups: control (C), APAP (2 g/kg), APAP + SP (500 mg/kg), and APAP + Silymarin (SM, 100 mg/kg) as positive control group. On the seventh day, the rats were sacrificed after taking blood samples. Then levels of biochemical parameters, oxidative stress markers and activity of antioxidant enzymes were measured. RESULTS: In the APAP group, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes activity was significantly increased and the level of protein carbonyl (PCO) was insignificantly increased as compared to control group. In addition, the activity of glutathione peroxidase (GPX) and total thiol in the APAP group was significantly decreased compared to the normal rats. Stachys pilifera. Benth extract administration significantly reduced the activity of AST and ALT enzymes and the level of PCO compared to the APAP group, while significantly elevated the activity of GPX enzyme. CONCLUSION: Hydroalcoholic extract of SP diminishes hepatotoxicity induced by APAP by reducing the amount of liver function indicators (AST and ALT). Furthermore, the hydroalcoholic extract of SP is capable of reducing oxidative stress through inhibiting protein oxidation as well as boosting the activity of GPX enzyme. In this respect, the hepatoprotective impact induced by the SP extract may possibly be attributable to its reactive oxygen species scavenging and antioxidant properties.

Activation of the Glutathione Peroxidase by Metformin in the Bile-duct Ligation induced Liver Injury: In vivo Combined with Molecular Docking Studies.

BACKGROUND: Inhibition of hepatic fibrosis is an attainable objective in managing the chronic liver disease. The present study aimed to investigate possible defensive effects of metformin on the activities of antioxidant enzymes, hydroxyproline content, and biochemical factors in bile duct ligation (BDL)-induced cholestatic rats. The interactive behavior of metformin with glutathione peroxidase (GPx) enzyme was also explained by molecular docking and conformation characterization. METHODS: The present study was conducted on 28-adult male Wistar rats classified into four 7-animal groups: sham-control, mere BDL, and BDL+ metformin that received daily metformin as gavage in two doses of 250 and 500 mg/kg bw for 10 days. Biochemical analysis, hydroxyproline content, and antioxidant enzymes activity were also determined. RESULTS: The hydroxyproline content significantly increased, but the GPx enzyme activity significantly decreased in the hepatic tissue following BDL, indicating that an oxidative stress-related model in rats was successfully constituted. Administration of metformin at two doses attenuated hydroxyproline content in the cholestatic liver and ameliorated the depletion of GPx enzyme activities compared to the non-treated BDL group (P-value ≤ 0.05). Molecular docking study provides the evidence for metformin ability to regulate enzymatic activity of GPx. CONCLUSION: The research data indicated that due to novel hepatoprotective effects of metformin in an animal model with BDL-induced liver injury, it was a potential beneficial therapeutic agent for treating the cholestatic liver disease. The main mechanism might contribute to antioxidant actions, particularly via GPx enzyme.

Synthesis, antimicrobial evaluation and docking studies of some novel quinazolinone Schiff base derivatives.

The quinazolin-4(3H)-one structural motif possesses a wide spectrum of biological activities. DNA gyrase play an important role in induction of bacterial death. It has been shown that many quinazolin-4(3H)-one derivatives have antibacterial effects through inhibition of DNA gyrase. Based on this information we decided to synthesize novel quinazolinone Schiff base derivatives in order to evaluate their antibacterial effects. A series of novel quinazolinone Schiff base derivatives were designed and synthesized from benzoic acid. The potential DNA gyrase inhibitory activity of these compounds was investigated using in silico molecular docking simulation. All new synthesized derivatives were screened for their antimicrobial activities against three species of Gram-negative bacteria including Escherichia coli, Pseudomonas aeruginosa, Salmonella entritidis and three species of Gram-positive bacteria comprising of Staphylococcus aurous, Bacillus subtilis, Listeria monocitogenes as well as for antifungal activities against Candida albicans using the conventional micro dilution method. Most of the compounds have shown good antibacterial activities, especially against E. coli at 128 µg/mL concentration while no remarkable antifungal activities were observed for these compounds. All the synthesized compounds exhibit dock score values between -5.96 and -8.58 kcal/mol. The highest dock score among them was -8.58 kcal/mol for compound 4c.

Exploring the interaction between epidermal growth factor receptor tyrosine kinase and some of the synthesized inhibitors using combination of in-silico and in-vitro cytotoxicity methods.

Quinazoline derivatives are potent inhibitors of human epidermal growth factor receptor (EGFR) as anticancer agents. In this study, the cytotoxic effects of a new series of synthesized quinazoline derivatives were evaluated using MTT assay against MCF-7 and HT-29 cell lines. Using molecular docking, the binding modes of all compounds were analyzed at the binding site of EGFR. Based on the results, the compounds L1, L2, L4, L5, L6, L7, L10, L15, and L18 may be promising EGFR inhibitors based on docking score and hydrogen bonds. Consistent with the experimental data, Met769 is recognized as a key residue in the binding of potential inhibitors. According to the MTT cytotoxicity assays, Lipinski's rule of five (RO5), absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters, and docking studies, three compounds L4, L15, and L10 with IC50 values of 80, 60, and 1 µM against the MCF-7 were selected for further comparative assessments. The dynamics of free EGFR, and selected ligand-EGFR complexes were investigated using molecular dynamics (MD) simulation studies. The results indicated that the three compounds bound to EGFR active site in a stable manner during the simulation through the formation of new hydrogen bonds with Phe699, Leu694, Gly700, Lys721, Met769, Arg817, and Asp831 with the superiority of compound L15. These features can promote future drug candidate designing to produce better derivatives in the search for the anticancer agents.

Docking study, synthesis and antimicrobial evaluation of some novel 4-anilinoquinazoline derivatives.

A series of novel 4-anilinoquinazoline derivatives were designed and synthesized from benzoic acid through ring closure, chlorination or nucleophilic substitution. The structures of compounds were characterized by IR, 1H-NMR and mass spectroscopy. All synthesized derivatives were screened for their antimicrobial activities against Gram-positive (Staphylococcus aurous, Bacillus subtilis, Listeria monocitogenes) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Salmonella entritidis) bacteria and also for antifungal activities against Candida albicans using the conventional micro dilution method. Most of the compounds have shown good antibacterial activities, especially compound 4c having highest activities against E. coli at 32 µg/mL concentration while the tested compounds did not exhibited remarkable antifungal activities. The potential DNA gyrase inhibitory activity of these compounds was investigated in silico using molecular docking simulation method. All compounds showed good results especially compound 4c which showed the lowest ΔGbind results (-8.16 Kcal/mol).

Characterization of adenosine receptor in its native environment: insights from molecular dynamics simulations of palmitoylated/glycosylated, membrane-integrated human A(2B) adenosine receptor.

Selective A(2B) receptor antagonists and agonists may play a role in important pathologies such as gastrointestinal, neurological (i.e., Alzheimer disease and dementia) and hypersensitive disorders (i.e., asthma), diabetes, atherosclerosis, restenosis and cancer. Hence, it is regarded as a good target for the development of clinically useful agents. In this study, the effects of lipid bilayer, N-acetylglucosamine and S-palmitoyl on the dynamic behavior of A(2B)AR model is explored. Homology modeling, molecular docking and molecular dynamics simulations were performed to explore structural features of A(2B)AR in the presence of lipid bilayer. Twenty ns MD simulation was performed on the constructed model inserted in a hydrated lipid bilayer to examine stability of the best model. OSIP339391 as the most potent antagonist was docked in the active site of the model. Another MD simulation was performed on the ligand-protein complex to explore effects of the bilayer on this complex. A similar procedure was performed for the modified protein with N-acetylglucosamine and S-palmitoyl moieties in its structure. Phe173 and Glu174 located in EL2 were determined to be involved in ligand-receptor interactions through π-π stacking and hydrogen bonding. Asn254 was crucial to form hydrogen-bonding. The reliability of the model was assessed through docking using both commercial and synthetic antagonists and an r(2) of 0.70 was achieved. Our results show that molecular dynamics simulations of palmitoylated/glycosylated, membrane-integrated human A(2B)AR in its native environment is a possible approach and this model can be used for designing potent and selective A(2B)AR antagonists.

Homology modeling of human CCR5 and analysis of its binding properties through molecular docking and molecular dynamics simulation.

In this study, homology modeling, molecular docking and molecular dynamics simulation were performed to explore structural features and binding mechanism of some inhibitors of chemokine receptor type 5 (CCR5), and to construct a model for designing new CCR5 inhibitors for preventing HIV attachment to the host cell. A homology modeling procedure was employed to construct a 3D model of CCR5. For this procedure, the X-ray crystal structure of bovine rhodopsin (1F88A) at 2.80Å resolution was used as template. After inserting the constructed model into a hydrated lipid bilayer, a 20ns molecular dynamics (MD) simulation was performed on the whole system. After reaching the equilibrium, twenty-four CCR5 inhibitors were docked in the active site of the obtained model. The binding models of the investigated antagonists indicate the mechanism of binding of the studied compounds to the CCR5 obviously. Moreover, 3D pictures of inhibitor-protein complex provided precious data regarding the binding orientation of each antagonist into the active site of this protein. One additional 20 ns MD simulation was performed on the initial structure of the CCR5-ligand 21 complex, resulted from the previous docking calculations, embedded in a hydrated POPE bilayer to explore the effects of the presence of lipid bilayer in the vicinity of CCR5-ligand complex. This article is part of a Special Issue entitled Protein translocation across or insertion into membranes.