scholarly journals Bioguided Isolation of Cyclopenin Analogues as Potential SARS-CoV-2 Mpro Inhibitors from Penicillium citrinum TDPEF34

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1366
Author(s):  
Bathini Thissera ◽  
Ahmed M. Sayed ◽  
Marwa H. A. Hassan ◽  
Sayed F. Abdelwahab ◽  
Ngozi Amaeze ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Structural Information ◽  
Positive Control ◽  
Penicillium Citrinum ◽  
Moderate Activity ◽  
Enzyme Active Site ◽  
Drug Candidates ◽  
Ic50 Values

SARS-CoV-2 virus mutations might increase its virulence, and thus the severity and duration of the ongoing pandemic. Global drug discovery campaigns have successfully developed several vaccines to reduce the number of infections by the virus. However, finding a small molecule pharmaceutical that is effective in inhibiting SARS-CoV-2 remains a challenge. Natural products are the origin of many currently used pharmaceuticals and, for this reason, a library of in-house fungal extracts were screened to assess their potential to inhibit the main viral protease Mpro in vitro. The extract of Penicillium citrinum, TDPEF34, showed potential inhibition and was further analysed to identify potential Mpro inhibitors. Following bio-guided isolation, a series of benzodiazepine alkaloids cyclopenins with good-to-moderate activity against SARS-CoV-2 Mpro were identified. The mode of enzyme inhibition of these compounds was predicted by docking and molecular dynamic simulation. Compounds 1 (isolated as two conformers of S- and R-isomers), 2, and 4 were found to have promising in vitro inhibitory activity towards Mpro, with an IC50 values range of 0.36–0.89 µM comparable to the positive control GC376. The in silico investigation revealed compounds to achieve stable binding with the enzyme active site through multiple H-bonding and hydrophobic interactions. Additionally, the isolated compounds showed very good drug-likeness and ADMET properties. Our findings could be utilized in further in vitro and in vivo investigations to produce anti-SARS-CoV-2 drug candidates. These findings also provide critical structural information that could be used in the future for designing potent Mpro inhibitors.

scholarly journals Antioxidant and Hypoglycemic Properties of Seeds of Cucurbitaceae Family from Western Nepal

2019 ◽  
Vol 9 (2) ◽  
pp. 1-5
Author(s):  
Atisammodavardhana Kaundinnyayana ◽  
Anita G.C ◽  
Asmita Banstola ◽  
Kishwor Poudel ◽  
Nirmal Acharya ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Radical Scavenging ◽  
Ethanolic Extract ◽  
Positive Control ◽  
Lagenaria Siceraria ◽  
Benincasa Hispida ◽  
Ic50 Values ◽  
In Vitro Antioxidant Activity

Introduction: Diabetes mellitus is an endocrine and metabolic disorder characterized by the defect in insulin secretion or insulin action or both. The association between diabetes mellitus and oxidative stress is well established. Cucurbitaceae is the largest family containing 120 genera mostly grown for its sweet and juicy fruit in warm climates all over the world. In the present work ethanolic extracts of the seeds of Trichosanthes cucumerina Linn (Chichinno), Lagenaria siceraria (Lauka), Cucurbita pepo (Pharsi), Luffa aegiptiaca (Ghiraula), and Benincasa hispida (Kubindo) collected from Western Nepal has been evaluated for their in vitro antioxidant activity and in vivo hypoglycemic effects. Methods: In vitro antioxidant activity was assessed by using DPPH free radical scavenging activities and their IC50 values were calculated. In vivo hypoglycemic effect was examined on normoglycemic rats. The clinical significance of ethanolic extract at the doses of 250 and 500 mg/kg body weight was investigated in 0, 30, 60, 120 and 180 minutes of oral administration. Metformin treated group was used as the positive control. Results: For DPPH radical scavenging action, the IC50 values of Trichosanthes cucumerina, Luffa aegiptiaca, Benincasa  hispida, Cucurbita pepo, Lagenaria siceraria were found to be 60.72, 127.73, 49.63, 98.16 and 52.46 µg/ml respectively which were compared to the IC50 value of ascorbic acid (Positive control) which was found to be 38.11 µg/ml. The extracts of Benincasa hispida, and were having higher antioxidant activity and tested for in vivo hypoglycemic activity.In vivo administration of two doses of ethanolic extract of Lagenaria siceraria reduced the level of blood glucose while the best result was obtained at 250 mg/kg. Conclusions: Present study revealed promising antioxidant and hypoglycemic activity of ethanolic extract of Lagenaria siceraria. The further exploration of Lagenaria siceraria for its effective use in the traditional medicinal system is essential.

Neuroprotectıve Potential of the Tubers of Corydalis triternata Zucc. Growing in Turkey

2020 ◽  
Vol 42 (4) ◽  
pp. 515-515
Author(s):  
Mehtap K l c Mehtap K l c ◽  
Erdal Kaya Erdal Kaya ◽  
Ayhan Ibrahim Aysal Ayhan Ibrahim Aysal ◽  
Bilge Sener Bilge Sener
Keyword(s):  
Metabolite Profile ◽  
Positive Control ◽  
Anticholinesterase Activity ◽  
Ex Situ ◽  
In Vitro Tests ◽  
Drug Candidates ◽  
Ic50 Value ◽  
Ic50 Values ◽  
Tof Ms

The continuing research for the determination of bioactive secondary metabolites from Turkish geophytes as therapeutic agents for dementia is mainly based on the need for drug candidates affected to brain areas. In this study, the in vitro anticholinesterase activity of the alkaloidal fractions of the tubers of Corydalis triternata Zucc. was investigated for their neuroprotective potential. Furthermore, the content of the active alkaloid fractions of the tubers was determined by LC-Q-TOF-MS. The tubers of Corydalis triternata Zucc. were collected from Hatay province of Turkey. The plant species were also preserved as ex-situ in Yalova-Turkey. The alkaloidal extract was prepared from the tubers. The anticholinesterase activities of the extracts and fractions were tested by modification of the Ellman’s method. The optimization of LC-MS conditions was used in ESI in the positive ion mode. The in vitro tests were highlighted that the alkaloidal extract of the tubers exhibited the highest activity against AChE and BuChE with IC50 values of 17.56 and#177; 1.0 g/mL and 326.23 and#177; 2.6 g /mL (galanthamine 6.8 and#177; 0.5 g /mL and 344.4 and#177; 8.2 g /mL as positive control), respectively. The fractions CK-3 and 4 were showed the highest inhibitory activity against AChE with the IC50 value (6.88 and#177; 0.3 g mL and 7.26 and#177; 0.3 g /mL), the fractions CK-5,6,7 and 8 have indicated potent inhibitory activities by compared with galanthamine, which was used as positive control with IC50 value 6.8 and#177; 0.5 g /mL. Among the fractions obtained from the alkaloidal extract, protoberberine-type alkaloids were exerted the most promising activity against both cholinesterases. The present study was described for the first time the in vitro anticholinesterase activity of Corydalis triternata Zucc. as neuroprotective potential and their metabolite profile by LC-Q-TOF-MS. Besides, the anticholinesterase assays on alkaloidal extract and its fractions showed that protoberberine-type alkaloids were determined the most potent inhibitor against AChE and BuChE.

scholarly journals Pharmacophore Investigations of Potential COVID-19 RNA Polymerase (Rdrp) Inhibitors: Repurposing FDA-Approved Drugs

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Valentina L. Kouznetsova ◽  
Caroline Kellogg ◽  
Aidan Zhang ◽  
Mahidhar Tatineni ◽  
Mark A. Miller ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Hydrophobic Interactions ◽  
Pharmacophore Model ◽  
In Vivo Studies ◽  
Drug Candidates ◽  
Promising Target ◽  
Approved Drugs ◽  
Fda Approved Drugs

Authors: Valentina L. Kouznetsova, Caroline Kellogg, Aidan Zhang, Mahidhar Tatineni, Mark A. Miller, Igor F. Tsigelny Background: SARS-CoV-2 has caused tens of millions of infections worldwide and millions of deaths. Currently, no effective treatment has been identified against the virus. Of its viral proteins, the RNA-dependent RNA polymerase (RdRp) is a promising target for drug design because of its importance in the replication of the virus. Material and Methods: After the identification of an RdRp pocket site based on the crystal structure of the RdRp– nsp7–nsp8 complex and the triphosphate form of remdesivir (PDB ID: 7BV2), we created a pharmacophore model consisting of 11 different features. These features include two acceptors, three donors, one acceptor and donor, three donor or acceptor, and one hydrophobic; an excluded volume of R=1.1 Å was also added. We then ran a pharmacophore search on our conformational database (DB) of approximately 2500 FDA-approved drugs and 600 000 conformations to identify potential drug-candidates. To determine the drugs that bound the best, we conducted multi conformational docking of these results to the previously identified pocket site. Results: The pharmacophore search found 315 different potential inhibitors of RdRp, of which 85 were chosen based on the number of H-bonds and hydrophobic interactions in the best docking pose. Several of the drugs selected, including ritonavir, dasatinib, imatinib, and sofosbuvir, have previously been shown to be effective against other viruses. Conclusions: These findings highlight compounds that could lead to both in vitro and in vivo studies to identify potential treatments against SARS-CoV-2.

scholarly journals HYPOGLYCEMIC ACTIVITY OF FRUITING BODY EXTRACTS FROM Pycnoporus sanguineus (L.: Fr.) Murr. MUSHROOM

2018 ◽  
Vol 40 (3) ◽  
Author(s):  
Tran Duc Tuong ◽  
Duong Xuan Chu ◽  
Bui Thi Minh Dieu
Keyword(s):  
Fruiting Body ◽  
Inhibitory Activity ◽  
Ethanolic Extract ◽  
Positive Control ◽  
Hypoglycemic Activity ◽  
Alpha Amylase ◽  
Moderate Activity ◽  
Pycnoporus Sanguineus ◽  
Ic50 Values

ABSTRACT Alpha-amylase and α-glucosidase are two main enzymes involved in carbohydrate metabolism. Inhibition of α-amylase and α-glucosidase can be said as an effective treatment for delaying the absorption of glucose after meals in people with diabetes mellitus. The objective of the present study is to provide an in vitro evidence for the potential hypoglycemic activity via inhibitory activity of the ethanolic and aqueous extracts from fruiting bodies of Pycnoporus sanguineus mushroom on α-amylase and α-glucosidase enzymes. Alpha-amylase and α-glucosidase inhibitory activities of aqueous and ethanolic extracts of P. sanguineus fruiting body were examined in a dose-response manner. Acarbose was used as a positive control. The results showed that the ethanolic extract of P. sanguineus possessed strong inhibitory activity on α-amylase and α-glucosidase with IC50 values of 97.08 and 92.60 μg/mL, respectively. The aqueous extract also exhibited moderate activity against α-amylase and α-glucosidase with IC50 values of 150.15 and 102.29 μg/mL, respectively. Which was significantly lower than that of acarbose with IC50 values of 85.12 and 68.36 μg/mL, respectively. The degree of α-amylase and α-glucosidase inhibition was correlated with the dose of inhibitors. From these results Pycnoporus sanguineus (Trametes sanguinea) possesses high potential in lowering blood glucose level, reduced insulin resistance and the risk of diabetic-related complications.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

2019 ◽  
Vol 26 (25) ◽  
pp. 4799-4831 ◽  
Author(s):  
Jiahua Cui ◽  
Xiaoyang Liu ◽  
Larry M.C. Chow
Keyword(s):  
Molecular Mechanisms ◽  
Metastatic Cancer ◽  
Drug Candidates ◽  
Chemical Structures ◽  
Transporter Family ◽  
Promising Area ◽  
New Generation ◽  
Nontoxic Inhibitors

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

Discovery of 3-Cinnamamido-N-Substituted Benzamides as Potential Antimalarial Agents

2020 ◽  
Vol 16 ◽  
Author(s):  
Haicheng Liu ◽  
Yushi Futamura ◽  
Honghai Wu ◽  
Aki Ishiyama ◽  
Taotao Zhang ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antimalarial Activity ◽  
In Vitro Assays ◽  
Compound Library ◽  
Antimalarial Agents ◽  
Phenotypic Screen ◽  
Ic50 Values ◽  
Substituted Benzamides

Background: Malaria is one of the most devastating parasitic diseases, yet the discovery of antimalarial agents remains profoundly challenging. Very few new antimalarials have been developed in the past 50 years, while the emergence of drug-resistance continues to appear. Objective: This study focuses on the discovery, design, synthesis, and antimalarial evaluation of 3-cinnamamido-N-substituted benzamides. Method: In this study, a screening of our compound library was carried out against the multidrug-sensitive Plasmodium falciparum 3D7 strain. Derivatives of the hit were designed, synthesized and tested against P. falciparum 3D7 and the in vivo antimalarial activity of the most active compounds was evaluated using the method of Peters’ 4-day suppressive test. Results: The retrieved hit compound 1 containing a 3-cinnamamido-N-substituted benzamide skeleton showed moderate antimalarial activity (IC50 = 1.20 µM) for the first time. A series of derivatives were then synthesized through a simple four-step workflow, and half of them exhibited slightly better antimalarial effect than the precursor 1 during the subsequent in vitro assays. Additionally, compounds 11, 23, 30 and 31 displayed potent activity with IC50 values of approximately 0.1 µM, and weak cytotoxicity against mammalian cells. However, in vivo antimalarial activity is not effective which might be ascribed to the poor solubility of these compounds. Conclusion: In this study, phenotypic screen of our compound library resulted in the first report of 3-cinnamamide framework with antimalarial activity and 40 derivatives were then designed and synthesized. Subsequent structure-activity studies showed that compounds 11, 23, 30 and 31 exhibited the most potent and selective activity against P. falciparum 3D7 strain with IC50 values around 0.1 µM. Our work herein sets another example of phenotypic screen-based drug discovery, leading to potentially promising candidates of novel antimalarial agents once given further optimization.

In Vitro and In Vivo Neutralizing Activity of Uvaria chamae Leaves Fractions on the Venom of Naja nigricollis in Albino Rat and Bovine Blood

2020 ◽  
Vol 14 (4) ◽  
pp. 295-311
Author(s):  
Ada Gabriel ◽  
Mamman Mohammed ◽  
Mohammed G. Magaji ◽  
Yusuf P. Ofemile ◽  
Ameh P. Matthew ◽  
...  
Keyword(s):  
Ethyl Acetate ◽  
Neglected Tropical Diseases ◽  
Lethal Dose ◽  
Positive Control ◽  
Haemolytic Activity ◽  
Cytotoxic Activities ◽  
Albino Rat ◽  
Aqueous Residue

Background: Snakebite envenomation is a global priority ranked top among other neglected tropical diseases. There is a folkloric claim that Uvaria chamae is beneficial for the management of snakebite and wounds in African ethnobotanical surveys. Besides, there are many registered patents asserting the health benefits of U. chamae. Objective: This study aimed to investigate U. chamae’s potentials and identify candidates for the development of tools for the treatment and management of N. nigricollis envenomation. Methods: Freshly collected U. chamae leaves were air-dried, powdered, and extracted in methanol. The median lethal dose of the extract was determined and further fractionated with n-hexane, n-butanol and ethyl acetate. Each fraction was tested for neutralizing effect against venom-induced haemolytic, fibrinolytic, hemorrhagic, and cytotoxic activities. Results: U. chamae fractions significantly (p<0.05) neutralized the haemolytic activity of N. nigricollis venom in n-butanol; 31.40%, n-hexane; 33%, aqueous residue; 39.60% and ethyl acetate; 40.70% at the concentration of 100mg/ml of each fraction against 10mg/ml of the snake venom when compared to the positive control. The fibrinolytic activity of N. nigricollis venom was significantly (p<0.05) neutralized in n-hexane at 73.88%, n-butanol; 72.22% and aqueous residue; 72.22% by the fractions of U. chamae. In addition, haemorrhagic activity of N. nigricollis venom was significantly (p<0.05) neutralized by U. chamae fractions at the concentrations of 100mg/ml, 200mg/ml and 400mg/ml except for n-butanol and aqueous residues at 400 mg/ml. Conclusion: U. chamae leaves fractions possess a high level of protection against N. nigricollis venoms-induced lethality and thus validate the pharmacological rationale for its usage in the management of N. nigricollis envenomation.

scholarly journals The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 873
Author(s):  
Raphael J. Eberle ◽  
Danilo S. Olivier ◽  
Marcos S. Amaral ◽  
Ian Gering ◽  
Dieter Willbold ◽  
...  
Keyword(s):  
Binding Mode ◽  
Drug Candidates ◽  
Main Protease ◽  
Ic50 Values ◽  
Repurposed Drugs ◽  
Antiparasitic Drugs ◽  
Inhibitory Potential ◽  
Dynamics Simulations ◽  
Micromolar Range

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

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