Molecular docking studies of some flavone analogues as α-Glucosidase inhibitors

Meena S.N., kumar U., Naik M.M., Ghadi S.C., Tilve S.G.

A synthetic flavone derivative 2-(benzo[d][1,3]dioxol-5-yl)-4H-chromen-4-one (BDC) was synthesized by the one pot reaction method and assessed for α-glucosidase inhibitory activity. The BDC demonstrated dose dependent inhibition of α-glucosidase activity. A maximum inhibition (99.3 ± 0.26%) of α-glucosidase was observed at 27.6 µM. The maximum α-glucosidase inhibitory activity depicted by BDC 27.6 µM concentration was 22.4 fold over the maximum inhibition observed with acarbose (97.72 ± 0.59% at 669.57 µM), a standard commercial anti-diabetic drug. In contrast to acarbose that depicted competitive type inhibition, kinetic studies of α-glucosidase inhibition by BDC demonstrated non-competitive inhibition with Km of 0.71 mM-1 and a Vmax of 0.028 mmol/min. In silico studies suggest allosteric interaction of BDC with α-glucosidase at a minimum binding energy (ΔG) of -8.64 kcal/mol and Ki of 465.3 nM, whereas, acarbose interacted at the active site of α-glucosidase with ΔG of -9.23 kcal/mol and Ki of 172 nM. Thus BDC significantly inhibited α-glucosidase in comparison to acarbose. Moreover, BDC has been endorsed for drug likeness by evaluating it as per Lipinski rule of five. Thus, BDC can be a lead compound for the management of type-2 diabetes mellitus.

Muller C.J., Malherbe C.J., Chellan N., Yagasaki K., Miura Y., Joubert E.

Risk factors of type 2 diabetes mellitus (T2D) and cardiovascular disease (CVD) cluster together and are termed the metabolic syndrome. Key factors driving the metabolic syndrome are inflammation, oxidative stress, insulin resistance (IR), and obesity. IR is defined as the impairment of insulin to achieve its physiological effects, resulting in glucose and lipid metabolic dysfunction in tissues such as muscle, fat, kidney, liver, and pancreatic β-cells. The potential of rooibos extract and its major C-glucosyl flavonoids, in particular aspalathin, a C-glucoside dihydrochalcone, as well as the phenolic precursor, Z-2-(β-D-glucopyranosyloxy)-3-phenylpropenoic acid, to prevent the metabolic syndrome, will be highlighted. The mechanisms whereby these phenolic compounds elicit positive effects on inflammation, cellular oxidative stress and transcription factors that regulate the expression of genes involved in glucose and lipid metabolism will be discussed in terms of their potential in ameliorating features of the metabolic syndrome and the development of serious metabolic disease. An overview of the phenolic composition of rooibos and the changes during processing will provide relevant background on this herbal tea, while a discussion of the bioavailability of the major rooibos C-glucosyl flavonoids will give insight into a key aspect of the bioefficacy of rooibos.

Semaan D.G., Igoli J.O., Young L., Marrero E., Gray A.I., Rowan E.G.

Ethno-botanical information from diabetic patients in Cuba led to the identification of Allophylus cominia as a possible source of new drugs for the treatment of type 2 diabetes mellitus (T2-DM).Chemical characterization of the extracts from A. cominia was carried out using chromatographic and spectroscopic methods. The extracts were tested for their activity on PTP1B, DPPIV, α-glucosidase enzymes and α-amylase.The flavonoid rich fractions from A. cominia inhibited DPPIV enzyme (75.3±2.33%) at 30µg/ml and produced a concentration-dependent inhibition against DPPIV with a Ki value of 2.6µg/ml. At 30µg/ml, flavonoids and pheophytins extracts significantly inhibited PTP1B enzyme (100±2.6% and 68±1% respectively). The flavonoids, pheophytin A and pheophytin B fractions showed significant concentration-dependent inhibition against PTP1B with Ki values of 3µg/ml, 0.64µg/ml and 0.88µg/ml respectively. At 30µg/ml, the flavonoid fraction significantly inhibited α-glucosidase enzyme (86±0.3%) in a concentration-dependent pattern with a Ki value of 2µg/ml. None of the fractions showed significant effects on α-amylase. Fatty acids, tannins, pheophytins A and B, and a mixture of flavonoids were detected in the methanolic extract from A. cominia. The identified flavonoids were mearnsitrin, quercitrin, quercetin-3-alloside, and naringenin-7-glucoside.The pharmacological effects of the extracts from A. cominia earlier observed in experimental diabetic models was confirmed in this study. Thus a new drug or formulation for the treatment of T2-DM could be developed from A. cominia.

Ma H., Wang L., Niesen D.B., Cai A., Cho B.P., Tan W., Gu Q., Xu J., Seeram N.P.

Evaluation of the mechanisms of inhibitory activities of gallotannins containing a glucitol core (GCGs) on α-glucosidase.

Jhong C., Riyaphan J., Lin S., Chia Y., Weng C.

The alpha-glucosidase inhibitor is a common oral anti-diabetic drug used for controlling carbohydrates normally converted into simple sugars and absorbed by the intestines. However, some adverse clinical effects have been observed. The present study seeks an alternative drug that can regulate the hyperglycemia by down-regulating alpha-glucosidase and alpha-amylase activity by molecular docking approach to screen the hyperglycemia antagonist against alpha-glucosidase and alpha-amylase activities from the 47 natural compounds. The docking data showed that Curcumin, 16-hydroxy-cleroda-3,13-dine-16,15-olide (16-H), Docosanol, Tetracosanol, Antroquinonol, Berberine, Catechin, Quercetin, Actinodaphnine, and Rutin from 47 natural compounds had binding ability towards alpha-amylase and alpha-glucosidase as well. Curcumin had a better biding ability of alpha-amylase than the other natural compounds. Analyzed alpha-glucosidase activity reveals natural compound inhibitors (below 0.5 mM) are Curcumin, Actinodaphnine, 16-H, Quercetin, Berberine, and Catechin when compared to the commercial drug Acarbose (3 mM). A natural compound with alpha-amylase inhibitors (below 0.5 mM) includes Curcumin, Berberine, Docosanol, 16-H, Actinodaphnine/Tetracosanol, Catechin, and Quercetin when compared to Acarbose (1 mM). When taken together, the implication is that molecular docking is a fast and effective way to screen alpha-glucosidase and alpha-amylase inhibitors as lead compounds of natural sources isolated from medicinal plants.

Lee Y., Kim S., Kim J.Y., Arooj M., Kim S., Hwang S., Kim B., Park K.H., Lee K.W.

Stilbene urea derivatives as a novel and competitive class of non-glycosidic α-glucosidase inhibitors are effective for the treatment of type II diabetes and obesity. The main purposes of our molecular modeling study are to explore the most suitable binding poses of stilbene derivatives with analyzing the binding affinity differences and finally to develop a pharmacophore model which would represents critical features responsible for α-glucosidase inhibitory activity. Three-dimensional structure of S. cerevisiae α-glucosidase was built by homology modeling method and the structure was used for the molecular docking study to find out the initial binding mode of compound 12, which is the most highly active one. The initial structure was subjected to molecular dynamics (MD) simulations for protein structure adjustment at compound 12-bound state. Based on the adjusted conformation, the more reasonable binding modes of the stilbene urea derivatives were obtained from molecular docking and MD simulations. The binding mode of the derivatives was validated by correlation analysis between experimental Ki value and interaction energy. Our results revealed that the binding modes of the potent inhibitors were engaged with important hydrogen bond, hydrophobic, and π-interactions. With the validated compound 12-bound structure obtained from combining approach of docking and MD simulation, a proper four featured pharmacophore model was generated. It was also validated by comparison of fit values with the Ki values. Thus, these results will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from stilbene derivatives.

Shams S., Hassan H., Ahmad A., Shah L., Ahmed N., Wadood A.

WANG C., CALWAY T.D., WEN X., SMITH J., YU C., WANG Y., MEHENDALE S.R., YUAN C.

Scutellaria baicalensis extract (SbE) has been shown to exert chemopreventive effects on several types of cancer. Baicalin, a hydrophilic flavonoid found in SbE, may have opposing effects that decrease the antitumor potential of SbE against colorectal cancer. In this study, after removing baicalin, we prepared an aglycone-rich fraction (ARF) of SbE and evaluated its anti-proliferative activity and mechanisms of action. The flavonoids found in ARF, baicalin fraction (BF) and SbE were determined by high-performance liquid chromatography (HPLC). The effects of ARF, BF, SbE and representative flavonoids on the proliferation of HCT-116 and HT-29 human colorectal cancer cells were determined by an MTS assay. The cell cycle, the expression of cyclins A and B1 and cell apoptosis were assayed using flow cytometry. Apoptosis-related gene expression was visualized by quantitative real-time polymerase chain reaction (PCR), and mitochondrial membrane potential was estimated following staining with JC-1. HPLC analysis showed that ARF contained two hydrophobic flavonoids, baicalein and wogonin, and that BF contained only baicalin. SbE had little anti-proliferative effect on the colorectal cancer cells; cancer cell growth was even observed at certain concentrations. ARF exerted potent anti-proliferative effects on the cancer cells. By contrast, BF increased cancer cell growth. ARF arrested cells in the S and G2/M phases, increased the expression of cyclins A and B1, and significantly induced cell apoptosis. Multiple genes in the mitochondrial pathway are involved in ARF-induced apoptosis, and subsequent cellular functional analysis validated the involvement of this pathway. These results suggest that removing baicalin from SbE produces an ARF that significantly inhibits the growth of colorectal cancer cells, and that the mitochondrial apoptotic pathway plays a role in hydrophobic flavonoid-induced apoptosis.

Zhang M., Liu L., Chen Y., Tian X., Qin J., Wang D., Li Z., Mo S.

Wogonin is one of the major constituents derived from Scutellaria Baicalensis, which has been reported to inhibit cell growth and/or induce apoptosis in various cancer cell lines. We aim to investigate the anticancer effects and associated mechanisms of wogonin on human multiple myeloma cell line in vitro.Effects of wogonin on the proliferation, cell cycle progression, and apoptosis of human myeloma cells were examined in vitro. The proteins associated with the biological effects of wogonin were analyzed by immunoblotting and immunocytochemical staining. In addition, the binding mode of wogonin within crystal structure of Akt1 protein was also evaluated by molecular docking analysis using the CDOCKER algorithm in Discovery Studio.Myeloma cell growth was attenuated by wogonin (70.4-352.0 μM) in a concentration-dependent manner. Cell cycle progression analysis and TUNEL assay showed that apoptosis was enhanced in wogonin-treated cells. Increased apoptosis was accompanied by decreased level of total-PARP, the arisen of PARP cleavage, significantly increased level of Bax protein and decreased level of Bcl-2 protein. Akt activity was suppressed and phosphorylation of Ser 473 residue was decreased in the wogonin-treated cells. Molecular docking analysis revealed wogonin could be stably docked into the ligand binding domain of Akt1 protein, and presented unique features of binding to Akt1, which indicated detailed interaction between wogonin and Akt signaling pathway.As wogonin was effective in vitro in promotion of apoptosis of myeloma cell by Akt-modulated, Bax and Bcl-2 related intrinsic apoptotic pathway, wogonin may be a potential therapeutic agent against multiple myeloma.

Voordeckers K., Brown C.A., Vanneste K., van der Zande E., Voet A., Maere S., Verstrepen K.J.

Resurrection of ancient fungal maltase enzymes uncovers the molecular details of how repeated gene duplications allow the evolution of protein variants with different functions.

Lefort É.C., Blay J.

Apigenin (4',5,7-trihydroxyflavone, 5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a flavonoid found in many fruits, vegetables, and herbs, the most abundant sources being the leafy herb parsley and dried flowers of chamomile. Present in dietary sources as a glycoside, it is cleaved in the gastrointestinal lumen to be absorbed and distributed as apigenin itself. For this reason, the epithelium of the gastrointestinal tract is exposed to higher concentrations of apigenin than tissues at other locations. This would also be true for epithelial cancers of the gastrointestinal tract. We consider the evidence for actions of apigenin that might hinder the ability of gastrointestinal cancers to progress and spread. Apigenin has been shown to inhibit cell growth, sensitize cancer cells to elimination by apoptosis, and hinder the development of blood vessels to serve the growing tumor. It also has actions that alter the relationship of the cancer cells with their microenvironment. Apigenin is able to reduce cancer cell glucose uptake, inhibit remodeling of the extracellular matrix, inhibit cell adhesion molecules that participate in cancer progression, and oppose chemokine signaling pathways that direct the course of metastasis into other locations. As such, apigenin may provide some additional benefit beyond existing drugs in slowing the emergence of metastatic disease.

Lawag I.L., Aguinaldo A.M., Naheed S., Mosihuzzaman M.

Antidesma bunius Spreng. (Phyllantaceae), Averrhoa bilimbi L. (Oxalidaceae), Biophytum sensitivum (L.) DC. (Oxalidaceae), Ceriops tagal (Perr.) C.B. Rob. (Rhizophoraceae), Kyllinga monocephala Rottb. (Cyperaceae), and Rhizophora mucronata Lam. (Rhizophoraceae) are used as remedies to control diabetes. In the present study, these plants were screened for their potential α-glucosidase inhibitory activity.The 80% aqueous ethanolic extracts were screened for their α-glucosidase enzyme inhibitory activity using yeast alpha glucosidase enzyme.Except for A. bilimbi with IC(50) at 519.86±3.07, all manifested a significant enzyme inhibitory activity. R. mucronata manifested the highest activity with IC(50) at 0.08±1.82 μg mL(-1), followed by C. tagal with IC(50) at 0.85±1.46 μg mL(-1) and B. sensitivum with IC(50) at 2.24±1.58 μg mL(-1).This is the first report on the α-glucosidase inhibitory effect of the six Philippine plants; thus, partly defining the mechanism on why these medicinal plants possess antidiabetic properties.

Verma A.K., Pratap R.

The syntheses of flavones with biologically important functional groups like C-glycoside, isoprenyl, and hydroxy functionalities at different positions available to medicinal chemists for SAR studies are reviewed. Some rearrangements and transformations facilitating the functionalization of flavones are also discussed.

Ninomiya M., Nishida K., Tanaka K., Watanabe K., Koketsu M.

Flavonoids are widely occurring polyphenols that are found in plants. The aim of this study was to investigate the structure–activity relationships of 5,7-dihydroxyflavones, with a focus on the effect of B ring structure substitution on the antiproliferative effects of the compounds in human leukemia HL-60 cells. We prepared a series of 5,7-dihydroxyflavones and evaluated their ability to inhibit the proliferation of HL-60 cells by using the MTT assay. The apoptosis- and cell differentiation-inducing ability of the most potent flavones were investigated using staining and morphological analyses. This study explored the antileukemic and chemopreventive potency of 5,7-dihydroxyflavones, particularly diosmetin and chrysoeriol, which have both hydroxy and methoxy groups on the B ring.

Hung H., Qian K., Morris-Natschke S.L., Hsu C., Lee K.

Covering: 2005 to 2010. This review covers recent discoveries of anti-diabetic compounds. Diabetes mellitus (DM) is a complex disease affecting patients' daily life and elevating patients' risk of developing other diseases. There are several forms of diabetes, including type-1 diabetes (insulin-dependent), type-2 diabetes (noninsulin-dependent), and gestational diabetes. Type-2 diabetes is the most common form and the patient population with type-2 DM rises every year. Current treatments meet some but not all patients' needs. Therefore, new anti-diabetic drugs are in great demand. Traditional herbal medicine provides a rich source for new drug discovery. In this review, recent discoveries of anti-diabetic compounds have been summarized according to their chemical structures and mechanisms of action. Anti-diabetic plant extracts, many of which have been used and marketed as dietary supplements, were also included and discussed, and are classified according to the positive control used in the anti-diabetic animal studies. New anti-diabetic natural products found in the recent patent literature are also summarized.

Sadeghi M., Miroliaei M., Ghanadian M., Szchumny A., Rahimmalek M.

Biflavonoids (BFs) are a group of polyphenols that have a unique biochemical structure. One of the key biomedical mechanisms that BFs can have high potential in managing Diabetes mellitus (DM) is α-glucosidase inhibition. Normally, elevated blood glucose levels are caused by high absorption of glucose in the epithelium of the small intestine. Since α-glucosidase helps increase the absorption of glucose in the small intestine in the final stage of glycan catabolism, inhibition of this essential biochemical process in diabetic patients can be considered a suitable approach in the treatment of this disease. The interaction between the BFs and α-glucosidase are still not clear, and need to be deeply investigated. Herein, the aim is to identify BFs with strong α-glucosidase inhibitory activity. Using docking-based virtual screening approach, the potential binding affinity of 18 selected BFs to α-glucosidase was evaluated. The dynamic activity and stability of α-glucosidase-BFs complexes were then measured by molecular dynamics simulation (MDs). "Strychnobiflavone" showed the best score in α-glucosidase inhibition. Arg315 and Phe303 involved in the interactions of α-glucosidase-strychnobiflavone complex through cation-π and π-π stacking, respectively. Based on in vitro kinetic studies, it was determined that the type of inhibition of "strychnobiflavone" corresponds to the pattern of mixed inhibitors. Furthermore, details of the interactions between strychnobiflavone and α-glucosidase were performed by in silico secondary structure content analysis. The findings showed when "strychnobifone" binds to the enzyme, significant alterations occur in the enzyme conformation affecting its catalytic activity. In general, the findings highlighted the potential of "strychnobiflavone" as a promising candidate for the treatment of diabetes mellitus through α-glucosidase inhibition. Further in vitro and in vivo studies have to confirm the therapeutic benefits of "strychnobiflavone" in conformational diseases such as diabetes mellitus.

Alagöz T., Çalişkan F.G., Bilgiçli H.G., Zengin M., Sadeghi M., Taslimi P., Gulçin İ.

AbstractA series of carvacrol‐based thiosemicarbazide (3a–e) and 1,3,4‐thiadiazole‐2‐amine (4a–e) were designed and synthesized for the first time. The structures were characterized by nuclear magnetic resonance and high resolution mass spectroscopy techniques. All compounds were examined for some metabolic enzyme activities. Results indicated that all the synthetic molecules exhibited powerful inhibitory actions against human carbonic anhydrase I and II (hCAI and II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes compared to the standard molecules. Ki values of five novel thiosemicarbazides and five new 1,3,4‐thiadiazole‐2‐amine derivatives (3a–e and 4a–e) for hCA I, hCA II, AChE, and BChE enzymes were obtained in the ranges 0.73–21.60, 0.42–15.08 µM, 3.48–81.48, 92.61–211.40 nM, respectively. After the experimental undertaking, an extensive molecular docking analysis was conducted to scrutinize the intricate details of interactions between the ligand and the enzyme in question. The principal focus of this investigation was to appraise the potency and efficacy of the most active compound. In this context, the calculated docking scores were noted to be remarkably low, with values of −8.65, −7.97, −8.92, and −8.32 kcal/mol being recorded for hCA I, hCA II, AChE, and BChE, respectively. These observations suggest a high affinity and specificity of the studied compounds toward the enzymes, as mentioned earlier, which may pave the way for novel therapeutic interventions aimed at modulating the activity of these enzymes.

Sanginabadi F., Gheibi N., Divsalar A., Saboury A.A., Yaghmaei P., Sadeghi M.

AbstractIn this work, the inhibitory ability and mechanism of ω3‐nicotinic acid (ω3‐NA) and ω3‐Picolinic acid (ω3‐PA) complexes on the activity of mushroom tyrosinase (MT) were scrutinized for progressing a novel MT inhibitor. The complexes were synthesized. It was shown to have a considerable inhibition on the MT activity and Ki value of ω3‐NA and ω3‐PA on MT equal to 5.2 and 5.1 mM, respectively. ω3‐NA and ω3‐PA inhibited MT with Vmax values in the range of 0.134 mM and 0.14 mM, respectively. The outputs obtained from fluorescence quenching specified that ω3‐NA and ω3‐PA could interact with MT. Especially, the decrease in fluorescence intensity was due to the formation of a ligand‐enzyme complex which was mostly motivated by hydrogen bonding and hydrophobic forces. The presence of ω3‐NA and ω3‐PA altered the structure of MT and reduced the α‐helix of the enzyme. Molecular docking investigation along with molecular dynamics simulation exhibited that ligands‐MT formation is directed by hydrogen binding with Trp136, His263, and Val299 residues. The results highlight that ω3‐NA and ω3‐PA can be considered as possible inhibitors in treating hyperpigmentation via MT enzyme inhibition.

Sadeghi M., Shakouri Khomartash M., Taslimi P.

AbstractInhibition of intestinal α‐glucosidase (αGS), a crucial enzyme in carbohydrate digestion, is an effective therapeutic approach for diabetes mellitus treatment. The C‐glycosylflavonoids (CGFs) are natural compounds with antioxidant, antidiabetic, and anti‐inflammatory activities. The present work seeks an alternative compound among CGFs that can control the blood glucose level by inhibiting αGS enzyme activity. Therefore, ten CGFs were selected and carried out the docking to αGS. The docking outcomes proposed that among selected CGFs, the orientin compound can successfully interact with the key residues of Asp215, Glu277, Asp352, Arg442, and Arg446. Of them, the orientin compound with docking energy of −6.11 Kcal/mol, was subsequently subjected to molecular dynamics simulation (MDs), and in vitro investigation. MDs results indicated that orientin formed a stable complex with αGS enzyme. We also performed molecular mechanics generalized Born and surface area (MM/GBSA) free energy calculation manner on all chosen CGFs along with miglitol as reference. The IC50 value of orientin for αGS inhibition with competitive mode was found to be 0.13 mg/ml. The results highlight that orientin can be considered as a possible compound in treating DM via αGS inhibition. However, further in vitro and in vivo analyses are required to confirm this claim.

Fatullayeva P.A., Mejidov A.A., Safronenko M.G., Nikolayevich Khrustalev V., Yalcin B., Sadeghian N., Sadeghi M., Taslimi P.

AbstractIn this study, (E)‐N′(3,5‐di‐tert‐butil‐2‐hedroxybenzilidene)‐2‐hydroxybenzohydrazide (H3sahz)2 and its copper (II) complex has been synthesized and evaluated by methods FTIR, UV–Vis, EPR, and single crystal X‐ray analysis. It has been shown, that H3sahz crystallizes as a dimer through hydrogen bonds. H3sahz with copper nitrate forms [Cu(H2sahz)(NO3)(H2O)] complex, which according to X‐ray diffraction analysis has a distorted square pyramidal structure. The complex was screened for α‐glucosidase (α‐Glu), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory abilities. Results displayed that IC50 and Ki values of the novel complex for AChE, BChE, and α‐Glu enzymes were obtained at 0.93–2.14, 1.01–2.03, and 73.86–102.65 μM, respectively. The molecular docking outcomes have shown that the synthetic complex has a lower affinity for α‐glucosidase compared to acarbose. But the inhibition ability of H3sahz for acetylcholinesterase and butyrylcholinesterase enzymes was greater than that of tacrine. These findings indicate that the (H3sahz)2 complex may be considered a possible candidate for the development and discovery of compounds effective in inhibiting the relevant enzymes.

Sadeghi M., Khomartash M.S., Gorgani-Firuzjaee S., Vahidi M., Khiavi F.M., Taslimi P.

Due to the presence of various phenolic compounds in D.sophia , this plant may have an inhibitory effect on α-Glc and ultimately diabetes control. Therefore, this work aims to scrutinize total phenolic, flavonoid contents, antioxidant capacity, and α-Glc inhibitory activity in aerial parts of methanolic D.sophia extract. The methanolic flower extracts were selected from among aerial parts for the experimental study of anti-diabetic effects by α-Glc inhibitory assays. The flower extracts were also studied by GC/MS to detect the compounds. The total phenolic and flavonoid contents were 21.38 ± 0.93 GAE/g and 96.2 ± 0.20 QE/g, respectively. The IC 50 value of flower extract for α-Glc inhibition with mixed (Competitive/non-competitive) mode was found to be 20.34 ± 0.11 mg/ml. Furthermore, in-vivo studies showed that the blood glucose level reduced after consumption of flower extract compared to the control group. Twenty-one compounds were identified by GC/MS technique. These compounds were assessed for high docking scores against α-Glc in silico. Docking score calculations exhibited that the DES-α-Glc complex had a significantly higher binding energy (-6.13 Kcal/mol) than other compounds. The DES-α-Glc complex which displayed a higher docking energy value than the ACR was subjected to MDs studies. The findings of this study suggest that the flower extract of D.sophia can be used as a suitable additive in syrups or foods with anti-diabetic capacity.

Dey D., Biswas P., Paul P., Mahmud S., Ema T.I., Khan A.A., Ahmed S.Z., Hasan M.M., Saikat A.S., Fatema B., Bibi S., Rahman M.A., Kim B.

Hepatitis C virus (HCV) infection is a major public health concern, and almost two million people are infected per year globally. This is occurred by the diverse spectrum of viral genotypes, which are directly associated with chronic liver disease (fibrosis, and cirrhosis). Indeed, the viral genome encodes three principal proteins as sequentially core, E1, and E2. Both E1 and E2 proteins play a crucial role in the attachment of the host system, but E2 plays a more fundamental role in attachment. The researchers have found the "E2-CD81 complex" at the entry site, and therefore, CD81 is the key receptor for HCV entrance in both humans, and chimpanzees. So, the researchers are trying to block the host CD81 receptor and halt the virus entry within the cellular system via plant-derived compounds. Perhaps that is why the current research protocol is designed to perform an in silico analysis of the flavonoid compounds for targeting the tetraspanin CD81 receptor of hepatocytes. To find out the best flavonoid compounds from our library, web-based tools (Swiss ADME, pKCSM), as well as computerized tools like the PyRx, PyMOL, BIOVIA Discovery Studio Visualizer, Ligplot+ V2.2, and YASARA were employed. For molecular docking studies, the flavonoid compounds docked with the targeted CD81 protein, and herein, the best-outperformed compounds are Taxifolin, Myricetin, Puerarin, Quercetin, and (-)-Epicatechin, and outstanding binding affinities are sequentially − 7.5, − 7.9, − 8.2, − 8.4, and − 8.5 kcal/mol, respectively. These compounds have possessed more interactions with the targeted protein. To validate the post docking data, we analyzed both 100 ns molecular dynamic simulation, and MM-PBSA via the YASARA simulator, and finally finds the more significant outcomes. It is concluded that in the future, these compounds may become one of the most important alternative antiviral agents in the fight against HCV infection. It is suggested that further in vivo, and in vitro research studies should be done to support the conclusions of this in silico research workflow.

Sadeghi M., Miroliaei M., Taslimi P., Moradi M.

Human serum albumin (HSA) is an important carrier protein in plasma with various functions, and it is exposed to glycation. Alkaloids are diverse compounds that have showed different anti-glycation activities. The present study aimed to investigate the anti-glycation activity of thirty alkaloid compounds. First, the compounds were studied via Lipinski’s rule; then, among thirty alkaloids, twenty-three were further designated for docking study, using AutoDock program. Three compounds which provided the minimum docking score were selected for further assays. Jatrorrhizine displayed potential activity to inhibit the HSA glycation. The stability of the jatrorrhizine-HSA complex was confirmed by molecular dynamics simulation (MDs). To approve the efficacy of this compound, future in vitro and in vivo studies are required.

Sadeghi M., Miroliaei M.

Sadeghi M., Miroliaei M., Fateminasab F., Moradi M.

Inflammation is a natural protective response toward various simulators, including tissue damage or pathogens. The cyclooxygenase-2 (COX-2) is a very important protein in triggering pain and inflammation. Previous studies have claimed that Allium sativum offers a wide range of anti-inflammatory therapeutics for human consumption. Drug discovery is a complicated process, though in silico methods can make this procedure simpler and more cost-effective. At the current study, we performed the virtual screening of eight Allium sativum–derived compounds via molecular docking with COX-2 enzyme and confirmed the binding energy by docking score estimate followed by ADMET and drug-likeness investigation. The resulting highest-docking scored compound was exposed to molecular dynamics simulation (MDS) for evaluating stability of the docked enzyme-ligand complex and to gauge the oscillation and conformational alterations for the time of enzyme-ligand interaction. The factors of RMSD, RMSF, hydrogen bond interactions, and Rg after 100 ns of MDS proved the stability of alliin in the active site of COX-2 in comparison with celecoxib (CEL) as the control. Moreover, we investigated the binding affinity analysis of all compounds via MM/PBSA method. The results from this study suggest that alliin (a sulfuric compound) exhibits a higher binding affinity for the COX-2 enzyme compared to the other compounds and CEL. Alliin showed to be a possible anti-inflammatory therapeutic candidate for managing the inflammatory conditions.