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Background: Plasmodium falciparum dihydroorotate dehydrogenase (PfDODH) is one of the enzymes currently explored in the treatment of malaria. Although there is currently no clinically approved drug targeting PfDODH, many of the compounds in clinical trials have [1, 2, 4,] triazolo [1, 5-a] pyrimidin- 7-amine backbone structure. Objective: This study sought to design new compounds from the fragments of known experimental inhibitors of PfDODH. Methods: Nine experimental compounds retrieved from Drug Bank online were downloaded and broken into fragments using the Schrodinger power shell; the fragments were recombined to generate new ligand structures using the BREED algorithm. The new compounds were docked with PfDODH crystal structure, after which the compounds were filtered with extensive drug-likeness and toxicity parameters. A 2D-QSAR model was built using the multiple linear regression method and externally validated. The electronic properties of the compounds were calculated using the density functional theory method. Results: Structural investigation of the six designed compounds, which had superior binding energies than the standard inhibitors, showed that five of them had [1, 2, 4,] triazolo [1, 5-a] pyrimidin-7-amine moieties and interacted with essential residues at the PfDODH binding site. In addition to their drug-like and pharmacokinetic properties, they also showed minimal toxicities. The externally validated 2D-QSAR model with R2 and Q2 values of 0.6852 and 0.6691 confirmed the inhibitory prowess of these compounds against PfDODH. The DFT calculations showed regions of the molecules prone to electrophilic and nucleophilic attacks. Conclusion: The current study thus provides insight into the development of a new set of potent PfDODH inhibitors.

Background: Oxidative stress is a significant player in the pathogenesis of diabetes mellitus and the Kelch-like ECH-associated protein1/nuclear factor erythroid 2-related factor 2/antioxidant response element (Keap1/Nrf2/ARE) signaling pathway serves as the essential defense system to mitigate oxidative stress. Nrf2 is responsible for the mitigation of oxidative stress while Keap1 represses Nrf2’s activation upon binding. Identification of Nrf2 activators has started to pick up enthusiasm as they can be used as therapeutic agents against diabetes mellitus. One of the ongoing mechanisms in the activation of Nrf2 is to disrupt Keap1/Nrf2 protein-protein interaction. This study aimed at using computational analysis to screen natural compounds capable of inhibiting Keap1/Nrf2 protein-protein interaction. Methods: A manual curated library of natural compounds was screened against crystal structure of Keap1 using glide docking algorithm. Binding free energy of the docked complexes, and adsorption, digestion, metabolism and excretion (ADME) properties were further employed to identify the hit compounds. The bioactivity of the identified hit against Keap1 was predicted using quantitative structure-activity relationship (QSAR) model. Results: A total of 7 natural compounds (Compound 222, 230, 310, 208, 210, 229 and 205) identified from different medicinal plants were found to be potent against Keap1 based on their binding affinity and binding free energy. The internal validated model kpls_radial_30 with R2 of 0.9109, Q2 of 0.7287 was used to predict the compounds’ bioactivities. Compound 205 was considered as the ideal drug candidate because it showed moderation for ADME properties, had predicted pIC50 of 6.614 and obeyed Lipinski’s rule of five. Conclusion: This study revealed that Compound 205, a compound isolated from Amphipterygium adstringens is worth considering for further experimental analysis.

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, GSK3β, 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.

Background: P-21 activating kinase 4 (PAK4) is implicated in the poor prognosis of many cancers, especially in the progression of Triple Negative Breast Cancer (TNBC). The present study was aimed at designing some potential drug candidates as PAK4 inhibitors for breast cancer therapy. Objective: This study aimed to finding novel inhibitors of PAK4 from natural compounds using computational approach. Methods: An e-pharmacophore model was developed from docked PAK4-co-ligand complex and used to screen over a thousand natural compounds downloaded from BIOFACQUIM and NPASS databases to match a minimum of 5 sites for selected (ADDDHRR) hypothesis. The robustness of the virtual screening method was accessed by well-established methods including EF, ROC, BEDROC, AUAC, and the RIE. Compounds with fitness score greater than one were filtered by applying molecular docking (HTVS, SP, XP and Induced fit docking) and ADME prediction. Using Machine learning-based approach QSAR model was generated using Automated QSAR. The computed top model kpls_des_17 (R2= 0.8028, RMSE = 0.4884 and Q2 = 0.7661) was used to predict the pIC50 of the lead compounds. Internal and external validations were accessed to determine the predictive quality of the model. Finally, the binding free energy calculation was computed. Results: The robustness/predictive quality of the models was affirmed. The hits had better binding affinity than the reference drug and interacted with key amino acids for PAK4 inhibition. Overall, the present analysis yielded three potential inhibitors that are predicted to bind with PAK4 better than the reference drug tamoxifen. The three potent novel inhibitors, vitexin, emodin and ziganein recorded IFD score of -621.97 kcal/mol, -616.31 kcal/mol and -614.95 kcal/mol, respectively while showing moderation for ADME properties and inhibition constant. Conclusion: It is expected that the findings reported in this study may provide insight for designing effective and less toxic PAK4 inhibitors for triple negative breast cancer.

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. 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. Schrodinger suites was used for docking of C. albidum phytocompounds with insulin. Diabetic rats fed with CAFPP for thirteen days have their blood glucose lowered significantly (p

Background Mitochondria dysfunction is one of the clinical features of diabetes mellitus (DM), which is a hallmark of insulin resistance (IR). This study investigates the therapeutic effect of Momordica charantia nanoparticles on mitochondria biogenesis in diabetic-induced rats. Forty-two adult wistar rats (average weight of 189 ± 10.32) were grouped as follows: STZ (65 mg/kg), control group, STZ + silver nitrate (10 mg/kg), STZ + M. charantia silver nanoparticles (50 mg/kg), STZ + metformin (100 mg/kg), and STZ + M. charantia aqueous extract (100 mg/kg). DM was induced intraperitoneal using freshly prepared solution of STZ (65 mg/kg), and rats with fasting blood sugar (FBS) above 250 mg/dl after 72 h of induction were considered diabetic. Treatment started after the third day of induction and lasted for 11 days. Effect of M. charantia nanoparticles on glucose level and pancreatic expression of genes involved in mitochondria biogenesis (PGC-1α, AMPK, GSK-3β, PPARϒ), inflammation (IL-1B, TNFα) and glucose sensitivity (PI3K, AKT, PTEN Insulin and Glut2) were quantified using reverse-transcriptase polymerase chain reaction (RT-PCR). Results The results showed that M. charantia nanoparticles promote mitochondria biogenesis, glucose sensitivity and reverse inflammation in the pancreas of diabetes rat model through upregulation of PGC-1α, AMPK, PPARϒ, AKT, Insulin and Glut2 mRNA expression and downregulation of GSK-3β, PI3K, IL-1B and TNFα mRNA expression in the pancreas of diabetic rats. Conclusion This study thus concludes that M. charantia nanoparticles may provide effective therapeutics against mitochondria dysfunction in the pancreas of diabetic model.

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.

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.

Background: The recent outbreak of Coronavirus SARS-CoV-2 (Covid-19), which has rapidly spread around the world in about three months with tens of thousands of deaths recorded so far is a global concern. An urgent need for potential therapeutic intervention is of necessity. Mpro is an attractive druggable target for the development of anti-COVID-19 drug development. Methods: Compounds previously characterized by Melissa officinalis were queried against the main protease of coronavirus SARS-CoV-2 using a computational approach. Results: Melitric acid A and salvanolic acid A had higher affinity than lopinavir and ivermectin using both AutodockVina and XP docking algorithms. The computational approach was employed in the generation of the QSAR model using automated QSAR, and in the docking of ligands from Melissa officinalis with SARS-CoV-2 Mpro inhibitors. The best model obtained was KPLS_Radial_ 28 (R2 = 0.8548 and Q2=0.6474, which was used in predicting the bioactivity of the lead compounds. Molecular mechanics based MM-GBSA confirmed salvanolic acid A as the compound with the highest free energy and predicted bioactivity of 4.777; it interacted with His-41 of the catalytic dyad (Cys145-His41) of SARS-CoV-2 main protease (Mpro), as this may hinder the cutting of inactive viral protein into active ones capable of replication. Conclusion: Salvanolic acid A can be further evaluated as a potential Mpro inhibitor.

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.

Hyperlipidemia and hyperglycemia have been implicated in diabetes mellitus (DM) leading to complications such as nephropathy. Medicinal plants like Mormodica charantia (MC) have been used in the treatment of DM over the years but little is known about their mechanisms of action. This study used biotechnology tools to investigate and compare the effects of M. charantia silver nanoparticles (MCSNPs) with M. charantia extract on expressions of genes linked with nephrotoxicity, lipid and glucose metabolisms using reverse-transcriptase polymerase chain reaction (RT-PCR) in streptozotocin-induced diabetic rats. The genes investigated include kidney injury molecule-1 (KIM-1), 3-hydroxyl, 3-methyl glutaryl_coA reductase (HMG-CoA reductase), peroxisome proliferator-activated receptor alpha and gamma (PPARα and PPARγ). Synthesis of MCSNPs was done using 1 mM concentration of aqueous silver nitrate solution at ratio 1:9 (v/v). Experimental rats were induced intraperitoneally with streptozotocin (65 mg/kg) and divided into six groups viz: diabetic control; normal control; silver nitrate (10 mg/kg); MCSNPs (50 mg/kg); Metformin (100 mg/kg) and M. charantia fraction (100 mg/kg). Sacrifice was done after 12 days of treatment and RT-PCR was then used to investigate gene expressions in liver and kidney tissues of the rats. The expression of HMG-CoA reductase gene was significantly upregulated (p

Studies have shown that diesel exhaust particle (DEP), a typical air particulate matter (PM) component of diesel exhaust, exerts its toxic effects by inducing oxidative and pro-inflammatory effects. Naringenin is the predominant flavanone in citrus fruits and has been reported to possess antioxidant, anti-inflammatory, anti-carcinogenic, and anti-mutagenic effects. This study examined the effects of naringenin on the oxidative and inflammatory effects of DEP in aorta and heart of Wistar rats. Diesel exhaust particle collected from a vehicular source in Akure, Nigeria, was extracted in methanol, fractionated and characterized by GCMS. Forty male Wistar rats (80–90 g) were divided into 8 groups. These rats were exposed to either methanol extract of SRM 2975 (mSRM; 0.064 mg/kg) DEP or collected diesel exhaust particles (mDEP; 0.064 or 0.64 mg/kg) sample in the presence or absence of naringenin (50 mg/kg). Both the DEP extracts and naringenin (NAR) were administered by oral gavage. The molecular interactions of NAR with target proteins associated with DEP toxicity were determined using in silico approach. The results show that both mDEP and mSRM caused significant (p < 0.001) decrease in serum HDL but increase serum AST/ALT ratio, ALP, LDL, triacylglycerol (TG), total cholesterol (TC), tissue conjugated dienes (CD) and MDA levels. The extracts also significantly (p < 0.001) increased the expression of IL-1β, TNFα, NF-κB, IκB, and IκKB in the aorta and heart, but decreased Nrf2, HO1, and anti-inflammatory IL-10 mRNA levels when compared with control. Pretreatment with NAR significantly (p < 0.001) reversed all these DEP-induced effects in both tissues. In conclusion, naringenin has the potential to mitigate DEP-induced oxidative stress and inflammation and thus may serve as a therapeutic agent against air pollution-induced cardiovascular damage.

Detarium microcarpum is a legume tree of tropical Africa, widely known for its ethno-medicinal potentials. Previous studies have reported its rich contents of phytochemicals which could be linked to the bioactive principle of the plant. The in vitro antisickling properties of D. microcarpum stem bark was evaluated using blood samples obtained from thirty-five confirmed sickle cell disease patients using standard microscopic techniques. The research outcome showed that D. microcarpum extract inhibited sickling of red blood cells with a laudable mean difference compared to p-hydrozybenzoic acid (reference antisickling drug) which is a pure compound. To further expounds it’s mechanism of action, six compounds previously isolated from D. microcarpum stem bark and fruits was docked into the active sites of deoxy-hemoglobin (PDB ID: IGZX) and 2, 3-bisphosphoglycerate mutase (PDB ID: 1T8P) using Autodock Vina algorithm. Results from the in silico studies showed that oxokolavenic acid, 5α, 8α -2-oxokalavenic acid and Copalic acid exhibited the most favorable ligand–protein molecular interaction with deoxy-hemoglobin and 2,3-bisphosphoglycerate mutase when compared with the reference antisickling drug, hydroxyurea. The interaction of these compounds with deoxy-hemoglobin could alter hemoglobin conformation, favoring the relaxed state, thereby delaying/inhibiting hemoglobin polymerization and sickling. Their interactions with 2, 3-bisphosphoglycerate mutase could inhibit 2, 3-bisphosphoglycerate synthesis, thus delaying enhanced delivery of oxygen to tissues which is twice the case seen in sickle cell anemia. This clearly shows the possible mechanism of action of D. microcarpum and further substantiates the antisickling potential of these compounds derived from D. microcarpum leaves and fruits.

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

BackgroundMoonseed vine (Triclisia gilletiiStaner) in the family Menispermaceae is a robust creeper of up to 10 cm diameter, of the lowland dense rain forest. In Ondo State, located in the South Western part of Nigeria, the plant which is usually called Peshe is used for the management of renal-related ailments. The present study was undertaken to explore the efficacy ofTriclisia gilletii, a folkloric therapy in the management of renal-related ailment.ResultsPhenols, steroids, saponins, and flavonoids are present in the TGME with a total antioxidant capacity of (30.36 ± 1.90 (mg GAE/g extract), LD50greater than 5000 mg/kg b.w., and in vitro anti-nucleation activity (iC50 = 7.09 mg/mL). Calcium oxalate stone formation as a result of oxalate from ethane-1,2-diol was evident by hypocalcemia, and further electrolyte imbalance and decreased glomerular filtration rate. The enhanced oxidative milieu in hyperoxaluria was evident by increased MDA and PC and decreased enzymatic and non-enzymatic antioxidants as well as renal membrane enzymes activities. The renal histopathological study further emphasized oxalate-induced damage and the ameliorative potential of TGME.ConclusionThe abnormal biochemical, redox electrolyte, membrane integrity, and histological alterations were attenuated by TGME which affirms its usage as nephroprotectant.

Background: Incidence of diabetes Mellitus (DM) is on the rise with each passing year in spite of available therapies in the management of DM. Metformin, a standard antidiabetic drug, and gallic acid (GA) are some of the compounds with established antidiabetic properties. However, there is dearth of information on their combination on JAK/STAT signaling pathway and glutathione metabolism in diabetic model. This study investigated the combined effect of metformin and GA on diabetic rats. Methods: Forty male wistar rats were divided into 5 groups viz: diabetic control, normal control, Metformin (100 mg/kg), GA (100 mg/kg) and GA (100 mg/kg) + Metformin (100 mg/kg). Diabetes was induced by administration of 10% fructose for 14 days followed by injection of streptozotocin (40 mg/kg). The therapy was administered for a total of 21 days. The pancreatic mRNA expression of antioxidant genes (glutamate cysteine ligase catalytic subunits (GCLC), glutamate cysteine ligase modifier subunits (GCLM) and Glutathione Synthetase (GSS), inflammatory genes (tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and proteins of the Janus Kinase/ Signal Transducer and Activator of Transcription pathway (Janus Kinase (JAK), Signal Transducer and Activator of Transcription (STAT), were quantified using reverse-transcriptase polymerase chain reaction (RT-PCR). Metformin and GA were also docked with Insulin, GSS, and Janus Kinase 2 (JAK2) to determine their binding affinity. Results: Rats treated with co-administration of GA and metformin significantly (p

The incidence of liver dysfunction increases in diabetes due to insulin resistance and oxidative stress. Chromolaena odorata is a dominant medicinal plant used in traditional medicine as a remedy for many diseases, particularly diabetes mellitus but the underlying mechanism of the plants chemicals is yet to be documented. This study investigated possible mechanisms behind the folkloric use of C. odorata in the management of diabetes. The effect of this plant on genes linked with glucose metabolism and oxidative stress was investigated in the liver of diabetic rats. The rats were divided into diabetes control, normal control, C. odorata extract (200 mg/kg) and diabetic + C. odorata extract (200 gm/kg). Diabetes was induced in the rats by intraperitoneal injection of a buffered solution of STZ (65 mg/kg). Ethanolic extract of C. odorata leaves (200 mg/kg) was orally administered to the treatment groups for a period of three weeks. The mRNA expression of Glut2, glucokinase, Nrf2 and keap1 were quantified using RT-PCR. Molecular docking studies were further explored to denote compounds from C. odorata that might be responsible for its liver protective effect in diabetes. In the diabetic group, liver mRNA expressions of Glut2, glucokinase and Nrf2 were down-regulated (p

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.

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.

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

Objective: Hesperidin (HSP) is a pharmacologically active organic compound found in citrus fruits and peppermint. We synthesized a new HSP derivative by reacting it with 5-Amino-1,3,4-thiadiazole-2-thiol in acetic acid. Methods: This compound was characterized by Fourier-transform infrared, proton nuclear magnetic resonance, and electron impact mass spectra. A molecular docking study explores the predicted binding of the compound and its possible mode of action. Bioavailability, site of absorption, drug mimic, and topological polar surface was predicted using absorption, distribution, metabolism, and excretion (ADME) studies. Results: The docking study predicts that the new compound binds to the active sites of Aurora-B and the MST3 pocket and has good ADME properties. Moreover, the thiazole ring and the presence of the electron releasing groups and hydrogen bond interaction with amino acid residues within the active sites play an important role in enhancing the antioxidant activity. Conclusion: In the present study, a new HSP derivative has been synthesized and characterized successfully and a theoretically promising antioxidant and anticytotoxic active agent introduced. We have shown the detailed binding analysis of 1,3,4-thiadiazol and hydrogen bonds with the inhibitor binding cavity of Aurora B and MST3. This could provide the development of some effective compounds against different diseases.

Background Annona muricata has been used in folklore in the management of diabetes. A major strategy in decreasing postprandial hyperglycemia in diabetes involves the inhibition of carbohydrate-hydrolyzing enzymes - α-amylase and α-glucosidase. Thus, this study evaluated the in vivo and in vitro inhibitory potentials of the different parts (fruit-pulp, leaf, stem-bark and root-bark) of Annona muricata. Methods A total of 120 Wistar rats were treated with methanol extracts for 28 days after which blood and tissue samples were collected for α-amylase assay. In vitro inhibitory properties of methanol, ethyl acetate and dichloromethane extracts of the various parts of the plant on α-amylase and α-glucosidase activities were performed using standard procedures. The mode and mechanism of interactions between the enzymes and extracts (and isolated acetogenin) were determined using various kinetic interpolations and in silico experiments. Result The fruit-pulp and root-bark methanolic extracts better -inhibited plasma and tissue amylase in vivo. The in vitro studies revealed that the stem-bark methanolic, fruit-pulp ethyl acetate, and leaf dichloromethane extracts, better inhibited α-amylase activity compared with the standard acarbose. Also, the leaf methanol, fruit-pulp ethyl acetate, and root-bark dichloromethane extract better inhibited α-glucosidase activity. These observations were corroborated with their higher Bmax and Vmax and lower Kd values. All the extracts exhibited an “uncompetitive” type of inhibition pattern. Also, the isolated acetogenin (15-acetyl guanacone) from the fruit-pulp showed a better binding affinity compared to the standard drug, Metformin. Conclusion Better natural remedy for diabetics can be obtained from Annona muricata with minimal or no adverse side effects.

Mitotic kinesin Eg5 remains a validated target in antimitotic therapy because of its essential role in the formation and maintenance of bipolar mitotic spindles. Although numerous Eg5 inhibitors of synthetic origin are known, only a few inhibitors derived from natural products have been reported. In our study, we focused on identifying novel Eg5 inhibitors from medicinal plants, particularly Garcinia species. Herein, we report the inhibitory effect of kolaflavanone (KLF), a Garcinia biflavonoid, on the ATPase and microtubule-gliding activities of mitotic kinesin Eg5. Additionally, we showed the interaction mechanism between Eg5 and KLF via in vitro and in silico analyses. The results revealed that KLF inhibited both the basal and microtubule-activated ATPase activities of Eg5. The inhibitory mechanism is allosteric, without a direct competition with adenosine-5′-diphosphate for the nucleotide-binding site. KLF also suppressed the microtubule gliding of Eg5 in vitro. The Eg5–KLF model obtained from molecular docking showed that the biflavonoid exists within the α2/α3/L5 (α2: Lys111–Glu116 and Ile135–Asp149, α3: Asn206–Thr226; L5: Gly117–Gly134) pocket, with a binding pose comparable to known Eg5 inhibitors. Overall, our data suggest that KLF is a novel allosteric inhibitor of mitotic kinesin Eg5.

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 Schrodinger 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.

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-β, JAK2, STAT3, STAT5, SOCS3, SOCS4 and glucokinase (GCK). Consequently, characterized compounds from M. charantia identified from literatures were docked with PI3K, JAK2 and TGF-β and STAT3 to retrieve potential hits. RESULTS: Oral administration of M. charantia nanoparticles (50 mg/kg) to STZ-induced diabetic untreated rats significantly ((p

Background: Obesity is a medical condition that occurs as a result of excess body fat which increases the risk of several metabolic disorders. Non-availability of efficient classical treatment for obesity has led to propose alternative treatment using plant material. Aim: To investigated the effect of saponin-rich extract of Lindackeria dentata (SLD) on obesity and some specific genes involved in inflammation and insulin resistance in the high-fat diet (HFD) on mice. Setting: The plant leaves were collected from farmland in Igede Ekiti, South-western Nigeria and authenticated at a herbarium unit of the Department of Plant Science and Biotechnology, Ekiti State University, Ado Ekiti, Nigeria. Methods: Saponin-rich extracts from Lindackeria dentata leaves were extracted using standard procedures, HFD was given to some selected mice for 12 weeks whilst monitoring blood glucose and body weight (bw) of the mice. Obese mice were treated orally with SLD 25 mg/kg, 50 mg/kg, 100 mg/kg and 200 mg/kg bw for 3 weeks, sacrificed, organs were collected and some biochemical assays were performed. Expression of some genes and histopathological study of the pancreas were also carried out using a standard scientific protocol. Results: Saponin-rich extract of Lindackeria dentata treatment significantly reduced ( p < 0.05) bw and adipose fat deposit, and caused partial restoration of pancreatic islet expansion (100 mg/kg and 200 mg/kg) coupled with accentuated regulation of leptin, insulin and IL-10 gene (25 mg/kg, 50 mg/kg and 100 mg/kg) when compared with control groups. Conclusion: The present data clearly showed that SLD could be a good intervention in the treatment of obesity and its attendant metabolic disorders.

Current sickle cell disease (SCD) therapies are limited and inefficient. The ethnomedicinal values of

Over activity of Glycogen synthase kinase-3β (GSK-3β), 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-3β 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-3β.

Alzheimer disease (AD) is the most common form of dementia contributing to about 60–70% of cases. β-Site amyloid precursor protein cleaving enzyme-1 (BACE1) plays an important role in the onset of AD and has become one of the important drug targets for AD. This approach has led to the development of promising BACE1 inhibitors, many of which are going through different phases of clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new drugs to uncover the mystery behind AD. This study focused on virtual screening of ~ 33,000 natural compounds to find potential BACE1 inhibitors. Multiple ligands pharmacophore model was generated using PHASE to screen retrieved compounds against a four-site (ADDR) hypothesis. Molecular docking was performed to predict the binding status of the natural compounds. Based on binding affinity, the top eight compounds were chosen for further analysis. The docked complexes were analyzed for binding free energy using PRIME MM/GBA calculation. The compounds were filtered for drug-likeness using ADME/TOX (absorption, distribution, metabolism, excretion and toxicity) prediction. AutoQSAR (automated quantitative structure activity relationship) was used to build a model for the prediction of compounds bioactivities. Despite retrieving a large number of compounds with favorable binding affinity, only a few were selected to be promising based on their ADME/TOX proprieties, binding free energy and predicted pIC50. This study identified four natural compounds (NPC469686, NPC262328, NPC29763 and NPC86744) as novel BACE1 inhibitors. The insights obtained from this study could be employed to produce next-generation drug for AD.

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.