Discovery of potential epidermal growth factor receptor inhibitors from black pepper for the treatment of lung cancer: an in-silico approach.

A tyrosine kinase receptor known as epidermal growth factor receptor (EGFR) is one of the main tumour markers in many cancer types and also plays a crucial role in cell proliferation, differentiation, angiogenesis, and apoptosis, which is a result of the auto-phosphorylations (kinase activity enhancement) that trigger signals involved in different cellular processes. Due to the discovery that non-small cell lung cancer (NSCLC) is a cause of this kinase activity enhancement, so far, several inhibitors have been tested against EGFR, but the side effects of these inhibitors necessitate an urgent measure to come up with an inhibitor that will be more specific to the cancer cells and not affect self-cells. This study was conducted to evaluate the efficacy of 37 compounds derived from Piper nigrum against EGFR using computer-aided drug design. Based on molecular docking, induced-fit docking, calculation of free binding energy, pharmacokinetics, QSAR prediction, and MD simulation. We propose five (5) lead compounds (clarkinol A, isodihydrofutoquinol B, Burchellin, kadsurin B, and lancifolin C) as a novel inhibitor, with clarkinol A demonstrating the highest binding affinity (-7.304 kcal/mol) with EGFR when compared with the standard drug (erlotinib). They also showed significant moderation for parameters investigated for a good pharmacokinetic profile, with a reliable R2 coefficient value predicted using QSAR models. The MD simulation of clarkinol A was found to be stable within the EGFR binding pocket throughout the 75 ns simulation run time. The findings showed that clarkinol A derived from Piper nigrum is worth further investigation and consideration as a possible EGFR inhibitor for the treatment of lung cancer. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00197-1.

Bambusa vulgaris leaves reverse mitochondria dysfunction in diabetic rats through modulation of mitochondria biogenic genes.

OBJECTIVES: There is evidence that mitochondrial dysfunction mediated by hyperglycemia increases the incidence of diabetes and age-related insulin resistance. Thus, maintaining mitochondrial integrity may provide alternative therapeutic approach in diabetes treatment. This study aimed to evaluate the effect of Bambusa vulgaris leaf extract on mitochondrial biogenesis in the pancreas of diabetic rats. METHODS: 11 weeks old male rats (n=30) were purchased, and sorted into the following groups: control, diabetic control, diabetes + metformin (100 mg/kg), diabetes + Aq. B. vulgaris (100 mg/kg), diabetes + Aq. B. vulgaris (200 mg/kg), and diabetes + Aq. B. vulgaris (300 mg/kg). Diabetes was induced in the rats by a single dose of 65 mg/kg streptozotocin (STZ). The mRNA expression of genes related to mitochondria biogenesis (pgc-1α, Nrf2, GSK3ß, AMPK and SIRT2) and genes of Nrf2-Keap1-ARE signaling pathway were determined by reverse transcriptase polymerase chain reaction. Molecular docking studies including lock and key docking and prime MM-GBSA were incorporated to identify the lead chemical compounds in Bambusa vulgari. RESULTS: The results showed that B. vulgaris leaf extract promotes mitochondrial biogenesis via altering the mRNA expression of mitochondrial master regulator pgc-1α, other upstream genes, and the Nrf2-Keap1-ARE antioxidant pathway. Through molecular docking results, cryptochlorogenic acid, hesperidin, orientin, vitexin, scopolin, and neochlorogenic were found as the crucial chemicals in B. vulgaris with the most modulating effect on PGC-1α, AMPK, and GSK3. CONCLUSIONS: This study thus suggests that B. vulgaris leaf extract restores the integrity of mitochondria in diabetic rats.

Hepatoprotective Effect of Morin Hydrate in Type 2 Diabetic Wistar Rats Exposed to Diesel Exhaust Particles.

Studies have shown that exposure to air pollutants such as diesel exhaust particles (DEP) exacerbate diabetes complications. Morin hydrate (MH), a plant bioflavonoid, provides hepatoprotection due to its diverse pharmacological properties. This study examines the hepatoprotective effects of MH in Wistar rats with type 2 diabetes exposed to diesel exhaust (DE). Procured male Wistar rats (n = 60) were separated into 12 groups of five rat each. Type 2 diabetes was induced following oral therapy with fructose solution and one-time injection of 45 mg/kg of streptozotocin (STZ). The DEP extract was administered by nasal instillation, whereas MH was administered via oral gavage. Biochemical assays were used to determine the effect of MH on diabetic rats and DEP-exposed diabetic rats with respect to liver function indices (AST and ALT), liver antioxidants (SOD, CAT, Gpx, and GSH), lipid profile, and oxidative stress marker (conjugated diene and lipid peroxidation). The mRNA expression of PI3K/AKT/GLUT4 and AMPK/GLUT4 signaling pathways were quantified using RT-PCR. The results show that normal rats, diabetic rats, and diabetic rats exposed to DEP exhibited a substantial decrease in oxidative stress indicators, serum lipid profile, and levels of AST and ALP, as well as an increase in liver natural antioxidants following oral administration of MH. The gene expression study demonstrated that MH promotes the activation of the insulin signaling pathways which facilitates the uptake of glucose from the blood. This study suggests that MH offered hepatoprotection in type 2 diabetic rats and DEP exposed diabetic rats.

Biochemical investigation of the upstream anti-sickling mechanisms of soursop (Annona muricata): 15-acetyl guanacone as an inhibitor of deoxyhaemoglobin polymerisation.

Current sickle cell disease (SCD) therapies are limited and inefficient. The ethnomedicinal values of Annona muricata in the treatment of SCD, leading to this present research. Leaves and fruits of Annona muricata were processed using solvent extraction and partitioning; aqueous, chloroform and ethyl acetate fractions. In vitro (anti-oxidant and anti-sickling), in silico, quantitative (amino acids) and kinetic simulation experiments were done. 15-acetyl guanacone, was used, in silico against 2,3-bisphosphoglycerate (2, 3-BPG) mutase and deoxyhaemoglobin. The ethyl acetate and chloroform fractions better NO● scavengers, iron-chelators and ferric reducing. In vitro unsickling (UT50) had ethyl acetate = 5 h and methanol = 7 h. Chloroform fraction had EC50 1.00 mg/mL (EC50 = 546 mg/mL) to 10.00 mg/mL (EC50 = 99 mg/mL). EC50 and IC50 of ethyl acetate fraction had steady-decrease. At higher concentration, chloroform fraction had higher Bmax (1.48 × 1021 U/mL) and higher Kd (3.66 × 1019 mg/mL), whereas, at a lower concentration, the ethyl acetate fraction demonstrated higher Bmax (7.23 × 1012 U/mL) and lower Kd (2.12 × 1011 mg/mL); The relative affinity (BP) of chloroform fraction increased progressively with concentration. The amino acid profile revealed rich concentrations glycine, valine, leucine, lysine, phenylalanine, histidine, arginine, and tryptophan. From the in silico experiments, 15-acetyl guanacone specifically targeted the A and B chains, with greater affinity for the beta subunit. This suggested that 15-acetyl guanacone might be able to prevent the polymerisation of deoxyHbSS, induce an allosteric conformational change that increases the oxygen affinity, and decrease the cellular 2, 3-BPG concentration.Communicated by Ramaswamy H. Sarma.

Virtual screening of natural compounds as selective inhibitors of polo-like kinase-1 at C-terminal polo box and N-terminal catalytic domain.

The over-expression of Polo-like kinase-1 (PLK1) is associated with cancer prognosis due to its pivotal role in cell proliferation. The N-terminal catalytic domain (NCD) and C-terminal polo box domain (PBD) of PLK1 are critical for the activity of the protein. Drugs that inhibit PLK1 by targeting these domains are on clinical trials, but so far, none has been approved by FDA. Thus, this study targets the two domains of PLK1 to identify compounds with inhibitory potential. Four validated e-pharmacophore models from NCD (PDB ID: 2OU7 and 4J52) and PBD (PDB ID: 5NEI and 5NN2) were used to screen over 26,000 natural compounds from NPASS database. Hits were identified after the well-fitted compounds were subjected to molecular docking study and ADME prediction. The pIC50 and electronic behaviour of the identified hits selectively targeting NCD and PBD of PLK1 were predicted via an externally validated QSAR model and quantum mechanics. The results showed that CAA180504, CAA197326, CAA74619, CAA328856 modulating PLK1 at NCD, and CBB130581, CBB230713, CBB206123, CBB12656 and CBB267117 modulating PLK1 at PBD had better molecular docking scores, pharmacokinetics and drug-like properties than NCD (volasertib) and PBD (purpurogallin) reference inhibitors. The compounds all had satisfactory inhibitory (pIC50) values which range from 6.187 to 7.157. The electronic behaviours of understudied compounds using HOMO/LUMO and global descriptive parameters revealed the atomic portion of the compounds prone to donating and accepting electrons. In conclusion, the hit compounds identified from the library of natural compounds are worthy of further experimental validation.Communicated by Ramaswamy H. Sarma.

Effect of Chrysophyllum albidum fruit pulp powder on antioxidant and proinflammatory genes in non-diabetic and type 2 diabetic rats.

BACKGROUND: Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia resulting from insulin deficiency or dysfunction. The imbalance between free radicals and antioxidants known as oxidative stress has been implicated in the pathogenesis and complications associated with DM. Chrysophyllum albidum is a seasonal fruit found to be rich in natural antioxidants. METHODS: DM was induced by high-fat diet dietary supplementation for 14 days followed by intraperitoneal injection of streptozotocin (35 mg/kg). Thirty-five experimental rats were then divided into seven groups viz.: non-diabetic control; diabetic control; metformin; diabetic and non-diabetic fed with 5 and 10% C. albidum fruit pulp powder (CAFPP). Fasting blood glucose was done with an automatic auto-analyzer and weights were monitored at three-day intervals. The expressions of Nrf2, SOD, CAT, GST, TNF-α, DPP4, and insulin were investigated using RT-PCR. Schrödinger suites was used for docking of C. albidum phytocompounds with insulin. RESULTS: Diabetic rats fed with CAFPP for thirteen days have their blood glucose lowered significantly (p < 0.05) and gained weight compared to diabetic control. CAFPP significantly (p < 0.05) up-regulated Nrf2, CAT, GST, SOD, and insulin genes expression in the diabetic group relative to diabetic control with concomitant down-regulation of TNF-α and DPP4 genes expression. Molecular docking of compounds previously characterized from C. albidum revealed that they are potent ligands of insulin receptors. CONCLUSION: The study revealed that CAFPP could be effective in the management of DM-related oxidative stress by up-regulating antioxidant and down-regulating pro-inflammatory genes expression. It also positively modulates genes associated with glucose metabolism. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-021-00921-0.

Molecular docking and pharmacokinetic studies of phytocompounds from Nigerian Medicinal Plants as promising inhibitory agents against SARS-CoV-2 methyltransferase (nsp16).

BACKGROUND: Since the index case was reported in China, COVID-19 has led to the death of at least 4 million people globally. Although there are some vaccine cocktails in circulation, the emergence of more virulent variants of SARS-CoV-2 may make the eradication of COVID-19 more difficult. Nsp16 is an S-adenosyl-L-Methionine-dependent methyltransferase that plays an important role in SARS-CoV-2 viral RNA cap formation-a crucial process that confers viral stability and prevents virus detection by cell innate immunity mechanisms. This unique property makes nsp16 a promising molecular target for COVID-19 drug design. Thus, this study aimed to identify potent phytocompounds that can effectively inhibit SARS-CoV-2 nsp16. We performed in silico pharmacokinetic screening and molecular docking studies using 100 phytocompounds-isolated from fourteen Nigerian plants-as ligands and nsp16 (PDB: 6YZ1) as the target. RESULTS: We found that only 59 phytocompounds passed the drug-likeness analysis test. However, after the docking analysis, only six phytocompounds (oxopowelline, andrographolide, deacetylbowdensine, 11, 12-dimethyl sageone, sageone, and quercetin) isolated from four Nigerian plants (Crinum jagus, Andrographis paniculata, Sage plants (Salvia officinalis L.), and Anacardium occidentale) showed good binding affinity with nsp16 at its active site with docking score ranging from - 7.9 to - 8.4 kcal/mol. CONCLUSIONS: Our findings suggest that the six phytocompounds could serve as therapeutic agents to prevent viral survival and replication in cells. However, further studies on the in vitro and in vivo inhibitory activities of these 6 hit phytocompounds against SARS-CoV-2 nsp16 are needed to confirm their efficacy and dose.

Identification of lead compounds from large natural product library targeting 3C-like protease of SARS-CoV-2 using E-pharmacophore modelling, QSAR and molecular dynamics simulation.

COVID-19 is a novel disease caused by SARS-CoV-2 and has made a catastrophic impact on the global economy. As it is, there is no officially FDA approved drug to alleviate the negative impact of SARS-CoV-2 on human health. Numerous drug targets for neutralizing coronavirus infection have been identified, among them is 3-chymotrypsin-like-protease (3CLpro), a viral protease responsible for the viral replication is chosen for this study. This study aimed at finding novel inhibitors of SARS-CoV-2 3C-like protease from the natural library using computational approaches. A total of 69,000 compounds from natural product library were screened to match a minimum of 3 features from the five sites e-pharmacophore model. Compounds with fitness score of 1.00 and above were consequently filtered by executing molecular docking studies via Glide docking algorithm. Qikprop also predicted the compounds drug-likeness and pharmacokinetic features; besides, the QSAR model built from KPLS analysis with radial as binary fingerprint was used to predict the compounds inhibition properties against SARS-CoV-2 3C-like protease. Fifty ns molecular dynamics (MD) simulation was carried out using GROMACS software to understand the dynamics of binding. Nine (9) lead compounds from the natural products library were discovered; seven among them were found to be more potent than lopinavir based on energies of binding. STOCK1N-98687 with docking score of -9.295 kcal/mol had considerable predicted bioactivity (4.427 µM) against SARS-CoV-2 3C-like protease and satisfactory drug-like features than the experimental drug lopinavir. Post-docking analysis by MM-GBSA confirmed the stability of STOCK1N-98687 bound 3CLpro crystal structure. MD simulation of STOCKIN-98687 with 3CLpro at 50 ns showed high stability and low fluctuation of the complex. This study revealed compound STOCK1N-98687 as potential 3CLpro inhibitor; therefore, a wet experiment is worth exploring to confirm the therapeutic potential of STOCK1N-98687 as an antiviral agent.

Newly designed compounds from scaffolds of known actives as inhibitors of survivin: computational analysis from the perspective of fragment-based drug design.

Survivin is an apoptosis suppressing protein linked to different forms of cancer. As it stands, there are no approved drugs for the inhibition of survivin in cancer cells despite a number of promising compounds in clinical trials. This study designed a new set of compounds from fragments of active survivin inhibitors to potentiate their binding with survivin at BIR domain. Three hundred and five (305) fragments made from eight potent inhibitors of survivin were reconstructed to form a new set of compounds. The compounds were optimized using R group enumeration and bioisostere replacement after extensive docking analysis. The optimised compounds were filtered by a validated pharmacophore model to reveal how well they are aligned to the pharmacophore sites. Molecular docking of the well aligned compounds revealed the top-scoring compounds; and these compounds were compared with the eight inhibitors used as template for fragment-based design on the basis of binding affinity (rigid and flexible docking), predicted pIC50 and intermolecular interactions. The electronic behaviours (global descriptors, HOMO/LUMO, molecular electrostatic potential and Fukui functions) of newly designed compounds were calculated to investigate their reactivity and atomic sites prone to neutrophilic/electrophilic attack. The nine newly designed compounds had better rigid and flexible docking scores, free energy of binding and intermolecular interactions with survivin at BIR domain than the eight active inhibitors. Based on frontier molecular orbitals, OPE-3 was found to be the most reactive and less stable compound (0.13194 eV), followed by OPE-4 and OPE-9. The global descriptive parameters showed that OPE-3 had highest softness value (7.5245 eV) while OPE-8 recorded the maximum hardness value (0.08486 eV). The well-validated QSAR model also showed that OPE-3, OPE-7 and OPE-8 had the most significant bioactivity of all the inhibitors. This study thus provides new insight into the design of compounds capable of modulating the activity of survivin. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00108-8.

Momordica charantia silver nanoparticles modulate SOCS/JAK/STAT and P13K/Akt/PTEN signalling pathways in the kidney of streptozotocin-induced diabetic rats.

OBJECTIVES: Diabetes nephropathy (DN) is one of the complications of diabetes mellitus (DM) marked by gradual progressive loss of renal function. SOCS/JAK/STAT and PI3K/Akt/PTEN signalling pathways are among the chain of interactions implicated in the onset, progression and pathology of DN. Momordica charantia (bitter melon) is often used in folk medicine as therapy for DM due to its hypoglycemic properties. This study was designed to evaluate M. charantia silver nanoparticles' therapeutic effect on DN-induced by streptozotocin (STZ) in Wistar rats. METHODS: The M. charantia nanoparticles used was synthesized using the filtrate from the plant methanolic extract added to 1 mM concentration of aqueous silver nitrate. DM was induced in Wistar rats by intraperitoneal injection of STZ (65 mg/kg). The animals' treatment groups were divided into; Diabetic control (65 mg/kg STZ), Control, and groups treated with silver nitrate (10 mg/kg), M. charantia nanoparticles (50 mg/kg), metformin (100 mg/kg), and plant extract (100 mg/kg). Treatment was terminated after 11 days. RT-PCR determined renal mRNA expression of Akt, PI3k, PTEN, TGF-ß, JAK2, STAT3, STAT5, SOCS3, SOCS4 and glucokinase (GCK). Consequently, characterized compounds from M. charantia identified from literatures were docked with PI3K, JAK2 and TGF-ß and STAT3 to retrieve potential hits. RESULTS: Oral administration of M. charantia nanoparticles (50 mg/kg) to STZ-induced diabetic untreated rats significantly ((p < 0.05) down-regulated the mRNA expression of Akt, PI3k, TGF-ß, JAK2, STAT3 and upregulated the mRNA expression of PTEN, SOCS3 and SOCS4, thus establishing the role of M. charantia nanoparticles in alleviating DN in diabetic rats. Additionally, there was a significant up-regulation of glucose metabolizing gene (glucokinase) upon administering M. charantia nanoparticles. Molecular docking results showed 12 compounds from bitter melon with docking score ranging from -6.114 kcal/mol to -8.221 kcal/mol that are likely to exert anti-diabetic properties. CONCLUSION: Observation drawn from this study suggests that M. charantia nanoparticles ameliorate DN through regulation of SOCS/JAK/STAT and PI3K/Akt/PTEN signalling pathways.

Exploring the antidiabetic potential of compounds isolated from Anacardium occidentale using computational aproach: ligand-based virtual screening.

Diabetes mellitus is becoming an important public health challenge worldwide and especially in developing nations. About 8.8 percent of the world adult population has been reported to have diabetes. Glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1) catalyses the first committed step in the pathway for biosynthesis of hexosamines in mammals, and its inhibition has been thought to prevent hyperglycaemia. Dipeptidyl peptidase-4 (DPP-4), on the other hand, degrades hormone glucagon-like peptide-1 (GLP-1), an enzyme that plays a major role in the enhancement of glucose-dependent insulin secretion, making these two proteins candidate targets for diabetes. To find potential inhibitors of DPP-4 and GFAT1 from Anacardium occidentale using a computational approach, glide XP (extra precision) docking, Induced Fit Docking (IFD), Binding free energy of the compounds were determined against prepared crystal structure of DPP-4 and GFAT1 using the Maestro molecular interface of Schrödinger suites. The Lipinski's rule of five (RO5) and ADME properties of the compounds were assessed. Predictive models for both protein targets were built using AutoQSAR. This study identified 8 hit compounds. Most of these compounds passed the RO5 and were within the recommended range for defined ADME parameters. In addition, the predicted pIC50 for the hit compounds were promising. The results obtained from the present study can be used to design an antidiabetic drug. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00084-z.

Saponins in Cancer Treatment: Current Progress and Future Prospects.

Saponins are steroidal or triterpenoid glycoside that is distinguished by the soap-forming nature. Different saponins have been characterized and purified and are gaining attention in cancer chemotherapy. Saponins possess high structural diversity, which is linked to the anticancer activities. Several studies have reported the role of saponins in cancer and the mechanism of actions, including cell-cycle arrest, antioxidant activity, cellular invasion inhibition, induction of apoptosis and autophagy. Despite the extensive research and significant anticancer effects of saponins, there are currently no known FDA-approved saponin-based anticancer drugs. This can be attributed to a number of limitations, including toxicities and drug-likeness properties. Recent studies have explored options such as combination therapy and drug delivery systems to ensure increased efficacy and decreased toxicity in saponin. This review discusses the current knowledge on different saponins, their anticancer activity and mechanisms of action, as well as promising research within the last two decades and recommendations for future studies.

Discovery of Traditional Chinese Medicine Derived Compounds as Wild Type and Mutant Plasmodium falciparum Dihydrofolate Reductase Inhibitors: Induced Fit Docking and ADME Studies.

BACKGROUND: In a bid to come up with effective compounds as inhibitors for antimalarial treatment, we built a library of 2,000 traditional Chinese medicine(TCM)-derived compounds retrieved from TCM Database@Taiwan. METHODS: The active sites of both the wild type and mutant Plasmodium falciparum dihydrofolatereductase (pfDHFR) were explored using computational tools. pfDHFR, one of the prime drug targets in the prevention of malaria infection induced by the female anopheles mosquito has continued to offer resistance to drugs (antifolates) due to mutation in some of the key amino acid residues crucial for its inhibition. RESULTS: We utilized virtual throughput screening and glide XP docking to screen the compounds, and 8 compounds were found to have promising docking scores with both the wild type and mutant pfDHFR. They were further subjected to Induce Fit Docking (IFD) to affirm their inhibitory potency. The ADME properties and biological activity spectrum of the compounds were also considered. The inhibition profile of the compounds revealed that a number of compounds formed intermolecular interactions with ASP54, ILE14, LEU164, SER108/ASN108, ARG122 and ASP58. Most of the compounds can be considered as drug candidates due to their antiprotozoal activities and accordance with the Lipinski's Rule of Five (ROF). CONCLUSION: The outcome of the present study should further be investigated to attest the efficacy of these compounds as better drug candidates than the antifolates.

Molecular docking studies, molecular dynamics and ADME/tox reveal therapeutic potentials of STOCK1N-69160 against papain-like protease of SARS-CoV-2.

SARS-CoV-2 is a new strain of Coronavirus that caused the pneumonia outbreak in Wuhan, China and has spread to over 200 countries of the world. It has received worldwide attention due to its virulence and high rate of infection. So far, several drugs have experimented against SARS-CoV-2, but the failure of these drugs to specifically interact with the viral protease necessitates urgent measure to boost up researches for the development of effective therapeutics against SARS-CoV-2. Papain-like protease (PLpro) of the viral polyproteins is essential for maturation and infectivity of the virus, making it one of the prime targets explored for SARS-CoV-2 drug design. This study was conducted to evaluate the efficacy of ~ 50,000 natural compounds retrieved from IBS database against COVID-19 PLpro using computer-aided drug design. Based on molecular dock scores, molecular interaction with active catalytic residues and molecular dynamics (MD) simulations studies, STOCK1N-69160 [(S)-2-((R)-4-((R)-2-amino-3-methylbutanamido)-3-(4-chlorophenyl) butanamido) propanoic acid hydrochloride] has been proposed as a novel inhibitor against COVID-19 PLpro. It demonstrated favourable docking score, the free energy of binding, interacted with key amino acid residues necessary for PLpro inhibition and also showed significant moderation for parameters investigated for ADME/tox (Adsorption, distribution, metabolism, excretion and toxicological) properties. The edge of the compound was further established by its stability in MD simulation conducted for 30 ns employing GROMACS software. We propose that STOCK1N-69160 is worth further investigation for preventing SARS-CoV-2.

Insight into glycogen synthase kinase-3ß inhibitory activity of phyto-constituents from Melissa officinalis: in silico studies.

Over activity of Glycogen synthase kinase-3ß (GSK-3ß), a serine/threonine-protein kinase has been implicated in a number of diseases including stroke, type II diabetes and Alzheimer disease (AD). This study aimed to find novel inhibitors of GSK-3ß from phyto-constituents of Melissa officinalis with the aid of computational analysis. Molecular docking, induced-fit docking (IFD), calculation of binding free energy via the MM-GBSA approach and Lipinski's rule of five (RO5) were employed to filter the compounds and determine their druggability. Most importantly, the compounds pIC50 were predicted by machine learning-based model generated by AutoQSAR algorithm. The generated model was validated to affirm its predictive model. The best model obtained was Model kpls_desc_38 (R2 = 0.8467 and Q2 = 0.8069), and this external validated model was utilized to predict the bioactivities of the lead compounds. While a number of characterized compounds from Melissa officinalis showed better docking score, binding free energy alongside adherence to RO5 than co-cystallized ligand, only three compounds (salvianolic acid C, ellagic acid and naringenin) showed more satisfactory pIC50. The results obtained in this study can be useful to design potent inhibitors of GSK-3ß.

Cymbopogon citratus (DC.) Stapf mitigates ER-stress induced by streptozotocin in rats via down-regulation of GRP78 and up-regulation of Nrf2 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Endoplasmic reticulum (ER) stress plays a role in the pathogenesis of diabetes mellitus, contributing to pancreatic dysfunction and insulin resistance. Ameliorating ER stress may be a viable therapeutic approach in the proper management of diabetes mellitus. Cymbopogon citratus (C.citratus) has been used in traditional medicine in the management of diabetes mellitus. Although well known for its anti-diabetic effect, the mechanism underlying this effect remains unclear. AIM OF THE STUDY: This study was designed to investigate the effect of C. citratus methanolic leaves extract on ER stress induced by streptozotocin (STZ) in wistar rats. MATERIALS AND METHODS: STZ (60 mg/kg) was used to induce ER stress in the pancreas of rats. The rats were administered C. citratus methanolic leaves extract via gastric gavage at doses 100, 200 and 400 mg/kg for two weeks while metformin (100 mg/kg) was used as positive control. Fasting blood glucose (FBG), expression of ER-stress related genes (GRP78, CHOP, ATF4, TRB3, PERK, IRE1), antioxidant (Nrf2 and AhR) and pro-inflammatory (TNF-α) genes were determined. Possible compounds responsible for this effect were also predicted through molecular docking. RESULTS: Induction of ER stress using STZ significantly increased FBG while administration of C. citratus methanolic extract restored it to normal control level (p < 0.05). Significant down-regulation of ER stress genes was observed upon treatment of ER stress induced rats with C. citratus methanolic extract when compared to ER-stress untreated rats. Significant up-regulation (p < 0.05) of genes coding for Nrf2 and AhR was also noticed upon treatment of ER stress induced rats with C. citratus methanolic extract. Molecular docking suggests that apigenin targets GRP78 with binding affinity of -9.3 kcal/mol while kaempferol and quercetin target Keap1 with binding affinity of -9.5 kcal/mol and may be responsible for this ameliorative effect on ER stress. CONCLUSION: These observations suggest that C. citratus mitigate ER stress induced by STZ via its down-regulative effect on GRP78 and up-regulative effect on NRF2 signaling.

Involvement of fat mass and obesity gene (FTO) in the anti-obesity action of Annona muricata Annonaceae: in silico and in vivo studies.

Background: Annona muricata (Annonaceae) known as soursop is a common tropical plant species known for its numerous medicinal properties including obesity. The underlying mechanism of anti-obesity effect of A. muricata was investigated. The fat mass and obesity associated protein (FTO) is a validated potential target for anti-obesity drugs. Methods: The interaction of compounds previously characterized from A. muricata was investigated against FTO using Autodock Vina. Also, modulation of FTO and STAT-3 mRNA expression by A. muricata was investigated in high fat diet induced obese rats (HFDR) using RT-PCR. Results: A significant up-regulation of FTO gene was observed in HFDR when compared to control rats, while administration of A. muricata (200 mg/kg) significantly (p < 0.05) down-regulated FTO gene expression when compared to HFDR group. The effect of obesity on STAT-3 gene expression was also reversed by A. muricata (200 mg/kg). In silico study revealed annonaine and annonioside (-9.2 kcal/mol) exhibited the highest binding affinity with FTO, followed by anonaine and isolaureline (-8.6 kcal/mol). Arg-96 is a critical amino acid enhancing anonaine, isolaureline-FTO binding. Conclusion: This study suggests the possible anti-obesity mechanism of A. muricata is via down-regulation of FTO with concomitant up-regulation of STAT-3 genes. This study confirmed the use of this plant in the management of obesity and the probable compounds responsible for its antiobesity effect are annonaine and annonioside.

Improvement of mitochondrial function by Tapinanthus globifer (A.Rich.) Tiegh. Against hepatotoxic agent in isolated rat's liver mitochondria.

ETHNOPHARMACOLOGICAL RELEVANCE: Disturbed mitochondrial function and energy crisis serve as key mechanisms for the development of liver injury. Hence, targeting cellular mitochondria in liver diseases might serve as a therapeutic option. Tapinanthus globifer (A.Rich.) Tiegh. has been used in traditional medicine in the management of liver disease. However, there is no scientific evidence supporting such use. AIM OF THE STUDY: The current investigation was designed to evaluate the protective role of Tapinanthus globifer treatment on the liver mitochondrial function after the induction of hepatotoxicity by the hepatotoxic agent Fe2+in vitro. MATERIALS AND METHODS: In this study, isolated mitochondria from rats' liver was incubated with Fe2+ (10 µM) for 1 h in the absence or presence of T. globifer (50, 100 and 200 µg/mL) metanolic extract (MVA). Mitochondrial viability, mitochondrial membrane potential (ΔΨm), mitochondrial swelling (MPTP)., total thiol content, lipid peroxidation (TBARS) and reactive oxygen species (ROS) production were measured. HPLC-DAD was used to identify potential phytochemicals in MVA. RESULTS: (MVA) was able to improve mitochondrial dysfunction induced by Fe2+, by attenuating MTT reduction, increased ΔΨm and mitochondrial swelling. Reduced total thiol and non-protein thiol contents which were associated with increased lipid peroxidation and ROS generation in Fe2+-treated mitochondria were significantly improved by MVA co-treatment. HPLC-DAD analysis revealed the presence of gallic acid, catechin, epigallocatechin, caffeic acid, rutin, glycoside flavonoid and quercetin in MVA that can be responsible for its beneficial effect. CONCLUSION: MVA phyto-compounds enhance mitochondrial redox signaling and possess mitochondrial function improving potential, thereby, providing scientific basis for its use in traditional medicine.

Possible involvement of transcriptional activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in the protective effect of caffeic acid on paraquat-induced oxidative damage in Drosophila melanogaster.

Paraquat (PQ) is a widely used herbicide with no antidote which is implicated in the pathogenesis of the Parkinson's disease. The present study then investigated the potential of caffeic acid (CA), a known antioxidant, cardioprotective and neuroprotective molecule to counteract oxidative stress mediated by PQ. In addition, molecular docking was performed to understand the mechanism underlying the inhibitory effect of CA against PQ poisoning. The fruit fly, Drosophila melanogaster, was exposed to PQ (0.44 mg/g of diet) in the absence or presence of CA (0.25, 0.5, 1 and 2 mg/g of died) for 7 days. Data showed that PQ-fed flies had higher incidence of mortality which was associated with mitochondrial dysfunction, increased free Fe(II) content and lipid peroxidation when compared to the control. Co-exposure with CA reduced mortality and markedly attenuated biochemical changes induced by PQ. The mechanism investigated using molecular docking revealed a strong interaction (-6.2 Kcal/mol) of CA with D. melanogaster transcriptional activation of nuclear factor erythroid 2-related factor 2 (Nrf2). This was characterized by the binding of CA to keap-1 domain of Nrf2. Taking together these results indicate the protective effect of CA against PQ-induced oxidative damage in D. melanogaster was likely through its coordination which hinders Nrf2-keap-1 binding leading to an increase of the antioxidant defense system.

Potential use of bitter melon (Momordica charantia) derived compounds as antidiabetics: In silico and in vivo studies.

Momordica charantia (bitter lemon) belongs to the cucurbitaceae family which has been extensively used in traditional medicines for the cure of various ailments such as cancer and diabetes. The underlying mechanism of M. charantia to maintain glycemic control was investigated. GLP-1 and DPP-4 gene modulation by M. charantia (5-20% inclusion in rats diet) was investigated in vivo by RT-PCR and possible compounds responsible for diabetic action predicted through in silico approach. Phytochemicalss previously characterized from M. charantia were docked into glucacon like peptide-1 receptor (GLP-1r), dipeptidyl peptidase (DPP4) and Takeda-G-protein-receptor-5 (TGR5) predicted using Autodock Vina. The results of the in silico suggests momordicosides D (ligand for TGR5), cucurbitacin (ligand for GLP-1r) and charantin (ligand for DPP-4) as the major antidiabetic compounds in bitter lemon leaf. M. charantia increased the expression of GLP-1 by about 295.7% with concomitant decreased in expression of DPP-4 by 87.2% with 20% inclusion in rat's diet. This study suggests that the mechanism underlying the action of these compounds is through activation of TGR5 and GLP-1 receptor with concurrent inhibition of DPP4. This study confirmed the use of this plant in diabetes management and the possible bioactive compounds responsible for its antidiabetic property are charantin, cucurbitacin and momordicoside D and all belong to the class of saponins.