Millet Derived Flavonoids as Potential SARS-CoV-2 Main Protease Inhibitors: A Computational Approach

10.26434/chemrxiv.12733622.v1 ◽

2020 ◽

Author(s):

Abhisek Mishra ◽

Sobha Chnadra Rath ◽

Iswar Baitharu ◽

Bhawani Prasad Bag

Keyword(s):

Drug Target ◽

Hiv Protease ◽

Binding Affinities ◽

Autodock Vina ◽

Major Health ◽

Main Protease ◽

Negative Effect ◽

Mutagenic Property

The on-going pandemic COVID-19 has emerged as a major health threat across the globe. At present, anti-viral drug discoveries are of great importance in combating the pandemic. Millets are known to contain numerous flavonoids with potential anti-viral properties. However, their anti-viral efficacy against SARS-CoV-2 is yet to be studied. The study uses the SARS-CoV-2 main protease (Mpro) as the potential drug target and docks with eleven millet derived flavonoids taking HIV protease inhibiting drugs nelfinavir and saquinavir as control. AutoDock Vina was used for assessing the binding affinities and strength of binding of flavonoids present in millets with the target protein Mpro. Further, the drug-likeness and pharmacokinetics properties of these flavonoids were analyzed using admetSAR. The ADMET analysis showed that isoorientin, orientin, vitexin, meletin, catechin, and myricetin possess potential mutagenic property while daidzein could have a negative effect on reproductive making these compounds as poor candidates for drug development against SARS-CoV-2. Based on the docking result and positive ADMET properties, the present study infers that apigenin may be considered as a potential inhibitor of SARS-CoV-2 Mpro and may be further investigated to test its anti-viral activities using in-vitro and in-vivo study.

Download Full-text

Millet Derived Flavonoids as Potential SARS-CoV-2 Main Protease Inhibitors: A Computational Approach

10.26434/chemrxiv.12733622.v2 ◽

2020 ◽

Author(s):

Abhisek Mishra ◽

Sobha Chnadra Rath ◽

Iswar Baitharu ◽

Bhawani Prasad Bag

Keyword(s):

Drug Target ◽

Hiv Protease ◽

Binding Affinities ◽

Autodock Vina ◽

Major Health ◽

Main Protease ◽

Negative Effect ◽

Mutagenic Property

The on-going pandemic COVID-19 has emerged as a major health threat across the globe. At present, anti-viral drug discoveries are of great importance in combating the pandemic. Millets are known to contain numerous flavonoids with potential anti-viral properties. However, their anti-viral efficacy against SARS-CoV-2 is yet to be studied. The study uses the SARS-CoV-2 main protease (Mpro) as the potential drug target and docks with eleven millet derived flavonoids taking HIV protease inhibiting drugs nelfinavir and saquinavir as control. AutoDock Vina was used for assessing the binding affinities and strength of binding of flavonoids present in millets with the target protein Mpro. Further, the drug-likeness and pharmacokinetics properties of these flavonoids were analyzed using admetSAR. The ADMET analysis showed that isoorientin, orientin, vitexin, meletin, catechin, and myricetin possess potential mutagenic property while daidzein could have a negative effect on reproductive making these compounds as poor candidates for drug development against SARS-CoV-2. Based on the docking result and positive ADMET properties, the present study infers that apigenin may be considered as a potential inhibitor of SARS-CoV-2 Mpro and may be further investigated to test its anti-viral activities using in-vitro and in-vivo study.

Download Full-text

Design of D-amino acids SARS-CoV-2 Main protease inhibitors using the cationic peptide from rattlesnake venom as a scaffold

10.1101/2021.11.10.468025 ◽

2021 ◽

Author(s):

Raphael J. Eberle ◽

Ian Gering ◽

Markus Tusche ◽

Philipp N. Ostermann ◽

Lisa Mueller ◽

...

Keyword(s):

Drug Target ◽

Cationic Peptide ◽

Uptake Inhibition ◽

Main Protease ◽

Target Molecules ◽

Crotalus Durissus ◽

3Cl Protease ◽

Inhibition Analysis

The C30 Endopeptidase (3C-like protease; 3CLpro) is essential for the life cycle of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) since it plays a pivotal role in viral replication and transcription and is hence a promising drug target. Molecules isolated from animals, insects, plants or microorganisms can serve as a scaffold for the design of novel biopharmaceutical products. Crotamine, a small cationic peptide from the venom of the rattlesnake Crotalus durissus terrificus has been the focus of many studies since it exhibits activities such as analgesic, in vitro antibacterial and hemolytic activities. The crotamine derivative L-peptides (L-CDP) that inhibit the 3CL protease in the low μM range were examined since they are susceptible to proteolytic degradation; we explored the utility of their D-enantiomers form. Comparative uptake inhibition analysis showed D-CDP as a promising prototype for a D-peptide-based drug. We also found that the D-peptides can impair SARS-CoV-2 replication in vivo, probably targeting the viral protease 3CLpro.

Download Full-text

The depressing (negative) effect of oestradiol benzoate on the in vitro secretion of LH and FSH by the pituitary gland of the LRH-pretreated long-term ovariectomized rat changes into the augmentative (positive) effect after discontinuation of the LRH-pretreatment

Acta Endocrinologica ◽

10.1530/acta.0.1100329 ◽

1985 ◽

Vol 110 (3) ◽

pp. 329-337 ◽

Cited By ~ 2

Author(s):

G. A. Schuiling ◽

H. Moes ◽

T. R. Koiter

Keyword(s):

Depressing Effect ◽

Ovx Rats ◽

Gonadotrophin Secretion ◽

Oestradiol Benzoate ◽

Negative Effect ◽

Positive Effect ◽

Perifusion System

Abstract. The effect of pretreatment in vivo with oestradiol benzoate on in vitro secretion of LH and FSH was studied in long-term ovariectomized (OVX) rats both at the end of a 5-day continuous in vivo pretreatment with LRH and 4-days after cessation of such LRH pretreatment. Rats were on day 0 sc implanted with osmotic minipumps which released LRH at the rate of 250 ng/h. Control rats were implanted with a piece of silicone elastomer with the dimensions of a minipump. On days 2 and 4 the rats were injected with either 3 μg EB or with oil. On day 5 part of the rats were decapitated and the in vitro autonomous (i.e. non-LRH-stimulated) and 'supra-maximally' LRHstimulated release of LH and FSH was studied using a perifusion system. From other rats the minipumps were removed on day 5 and perifusion was performed on day 9. On the 5th day of the in vivo LRH pretreatment the pituitary LH/FSH stores were partially depleted; the pituitaries of the EB-treated rats more so than those of the oil-injected rats. EB alone had no significant effect on the content of the pituitary LH- and FSH stores. On day 9, i.e. 4 days after removal of the minipumps, the pituitary LH and FSH contents had increased in both the oil- and the EB injected rats, but had not yet recovered to control values. In rats not subjected to the 5-days pretreatment with LRH EB had a positive effect on the supra-maximally LRH-stimulated secretion of LH and FSH as well as on the non-stimulated secretion of LH. EB had no effect on the non-stimulated secretion of FSH. After 5 days of in vivo pretreatment with LRH only, the in vitro non-stimulated and supra-maximally LRH-stimulated secretion of both LH and FSH were strongly impaired, the effect correlating well with the LRH-induced depletion of the pituitary LH/FSH stores. In such LRH-pretreated rats EB had on day 5 a negative effect on the (already depressed) LRH-stimulated secretion of LH (not on that of FSH). EB had no effect on the non-stimulated LH/FSH secretion. It could be demonstrated that the negative effect of the combined LRH/EB pretreatment was mainly due to the depressing effect of this treatment on the pituitary LH and FSH stores: the effect of oestradiol on the pituitary LRH-responsiveness (release as related to pituitary gonadotrophin content) remained positive. In LRH-pretreated rats, however, this positive effect of EB was smaller than in rats not pretreated with LRH. Four days after removal of the minipumps there was again a positive effect of EB on the LRH-stimulated secretion of LH and FSH as well as on the non-stimulated secretion of LH. The positive effect of EB on the pituitary LRH-responsiveness was as strong as in rats which had not been exposed to exogenous LRH. The non-stimulated secretion of FSH was again not affected by EB. The results demonstrate that the effect of EB on the oestrogen-sensitive components of gonadotrophin secretion consists of two components: an effect on the pituitary LRH-responsiveness proper, and an effect on the pituitary LH/FSH stores. The magnitude of the effect of EB on the LRH-responsiveness is LRH dependent: it is very weak (almost zero) in LRH-pretreated rats, but strong in rats not exposed to LRH as well as in rats of which the LRH-pretreatment was stopped 4 days previously. Similarly, the effect of EB on the pituitary LH and FSH stores is LRH-dependent: in the absence of LRH, EB has no influence on the contents of these stores, but EB can potentiate the depleting effect of LRH on the LH/FSH-stores. Also this effect disappear after cessation of the LRH-pretreatment.

Download Full-text

Associated microflora of medicinal ferns: biotechnological potentials and possible applications

International Journal of Bioassays ◽

10.21746/ijbio.2016.03.0017 ◽

2016 ◽

Vol 5 (03) ◽

pp. 4927 ◽

Cited By ~ 3

Author(s):

Shubhi Srivastava ◽

Paul A. K.

Keyword(s):

Secondary Metabolites ◽

Growth Promotion ◽

Biological Activities ◽

Hydrolytic Enzymes ◽

In Vitro Production ◽

Wide Range ◽

Negative Effect ◽

Bacteria And Fungi

Plant associated microorganisms that colonize the upper and internal tissues of roots, stems, leaves and flowers of healthy plants without causing any visible harmful or negative effect on their host. Diversity of microbes have been extensively studied in a wide variety of vascular plants and shown to promote plant establishment, growth and development and impart resistance against pathogenic infections. Ferns and their associated microbes have also attracted the attention of the scientific communities as sources of novel bioactive secondary metabolites. The ferns and fern alleles, which are well adapted to diverse environmental conditions, produce various secondary metabolites such as flavonoids, steroids, alkaloids, phenols, triterpenoid compounds, variety of amino acids and fatty acids along with some unique metabolites as adaptive features and are traditionally used for human health and medicine. In this review attention has been focused to prepare a comprehensive account of ethnomedicinal properties of some common ferns and fern alleles. Association of bacteria and fungi in the rhizosphere, phyllosphere and endosphere of these medicinally important ferns and their interaction with the host plant has been emphasized keeping in view their possible biotechnological potentials and applications. The processes of host-microbe interaction leading to establishment and colonization of endophytes are less-well characterized in comparison to rhizospheric and phyllospheric microflora. However, the endophytes are possessing same characteristics as rhizospheric and phyllospheric to stimulate the in vivo synthesis as well as in vitro production of secondary metabolites with a wide range of biological activities such as plant growth promotion by production of phytohormones, siderophores, fixation of nitrogen, and phosphate solubilization. Synthesis of pharmaceutically important products such as anticancer compounds, antioxidants, antimicrobials, antiviral substances and hydrolytic enzymes could be some of the promising areas of research and commercial exploitation.

Download Full-text

The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature

Genes ◽

10.3390/genes12060875 ◽

2021 ◽

Vol 12 (6) ◽

pp. 875

Author(s):

Karlijn Pellikaan ◽

Geeske M. van Woerden ◽

Lotte Kleinendorst ◽

Anna G. W. Rosenberg ◽

Bernhard Horsthemke ◽

...

Keyword(s):

Intellectual Disability ◽

Single Nucleotide Polymorphism Array ◽

Genetic Defect ◽

Missense Variant ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Pituitary Hormone ◽

Negative Effect

Prader–Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader–Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C>T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the ‘Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations’ (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype–phenotype relationship in PWS.

Download Full-text

Selection of Trichoderma spp. strains for the control of Sclerotinia sclerotiorum in soybean

Pesquisa Agropecuária Brasileira ◽

10.1590/s0100-204x2017001200002 ◽

2017 ◽

Vol 52 (12) ◽

pp. 1140-1148 ◽

Cited By ~ 7

Author(s):

Patrícia Elias Haddad ◽

Luis Garrigós Leite ◽

Cleusa Maria Mantovanello Lucon ◽

Ricardo Harakava

Keyword(s):

Sclerotinia Sclerotiorum ◽

Culture Medium ◽

Harmful Effect ◽

Soybean Seeds ◽

Trichoderma Spp ◽

Negative Effect ◽

Soybean Plants ◽

Selection Of

Abstract: The objective of this work was to evaluate, in vitro and in vivo, the potential of Trichoderma spp. strains to control Sclerotinia sclerotiorum in soybeans (Glycine max) and to perform the molecular identification of the best perfoming strains. The effect of 120 strains of Trichoderma spp. on the viability of S. sclerotiorum sclerotia was evaluated in vitro through immersion in suspension of conidia from the antagonists and plating in culture medium. The best performing strains were evaluated in vivo, in a greenhouse, for control of the pathogen inoculated on 'Pintado' soybean seeds and plants. Of the 120 strains tested in vitro, 22 strains of Trichoderma spp. caused 100% inhibition of sclerotia germination. In the greenhouse, five strains inhibited the negative effect of the pathogen on seed germination and two strains increased in up to 67% plant dry matter. The best performing strains were identified as T. koningiopsis (3 strains), T. asperelloides (3), T. atroviride (2), and T. virens (1). Trichoderma strains are able to protect soybean plants from the harmful effect of S. sclerotiorum and, at the same time, they can promote the growth of the aerial part in greenhouse conditions.

Download Full-text

A Possible Role of Allatostatin C in Inhibiting Ecdysone Biosynthesis Revealed in the Mud Crab Scylla paramamosain

Frontiers in Marine Science ◽

10.3389/fmars.2021.740251 ◽

2021 ◽

Vol 8 ◽

Author(s):

An Liu ◽

Wenyuan Shi ◽

Dongdong Lin ◽

Haihui Ye

Keyword(s):

Scylla Paramamosain ◽

Dependent Manner ◽

Mud Crab ◽

Methyl Farnesoate ◽

Independent Manner ◽

Wide Range ◽

Negative Effect

C-type allatostatins (C-type ASTs) are a family of structurally related neuropeptides found in a wide range of insects and crustaceans. To date, the C-type allatostatin receptor in crustaceans has not been deorphaned, and little is known about its physiological functions. In this study, we aimed to functionally define a C-type ASTs receptor in the mud crab, Scylla paramamosian. We showed that C-type ASTs receptor can be activated by ScypaAST-C peptide in a dose-independent manner and by ScypaAST-CCC peptide in a dose-dependent manner with an IC50 value of 6.683 nM. Subsequently, in vivo and in vitro experiments were performed to investigate the potential roles of ScypaAST-C and ScypaAST-CCC peptides in the regulation of ecdysone (20E) and methyl farnesoate (MF) biosynthesis. The results indicated that ScypaAST-C inhibited biosynthesis of 20E in the Y-organ, whereas ScypaAST-CCC had no effect on the production of 20E. In addition, qRT-PCR showed that both ScypaAST-C and ScypaAST-CCC significantly decreased the level of expression of the MF biosynthetic enzyme gene in the mandibular organ, suggesting that the two neuropeptides have a negative effect on the MF biosynthesis in mandibular organs. In conclusion, this study provided new insight into the physiological roles of AST-C in inhibiting ecdysone biosynthesis. Furthermore, it was revealed that AST-C family peptides might inhibit MF biosynthesis in crustaceans.

Download Full-text

Molecular Characterization of HOXA2 and HOXA3 Binding Properties

Journal of Developmental Biology ◽

10.3390/jdb9040055 ◽

2021 ◽

Vol 9 (4) ◽

pp. 55

Author(s):

Joshua Mallen ◽

Manisha Kalsan ◽

Peyman Zarrineh ◽

Laure Bridoux ◽

Shandar Ahmad ◽

...

Keyword(s):

Transcription Factors ◽

Molecular Characterization ◽

Sequence Motif ◽

Body Parts ◽

Binding Affinities ◽

Binding Properties ◽

Functional Consequences

The highly conserved HOX homeodomain (HD) transcription factors (TFs) establish the identity of different body parts along the antero–posterior axis of bilaterian animals. Segment diversification and the morphogenesis of different structures is achieved by generating precise patterns of HOX expression along the antero–posterior axis and by the ability of different HOX TFs to instruct unique and specific transcriptional programs. However, HOX binding properties in vitro, characterised by the recognition of similar AT-rich binding sequences, do not account for the ability of different HOX to instruct segment-specific transcriptional programs. To address this problem, we previously compared HOXA2 and HOXA3 binding in vivo. Here, we explore if sequence motif enrichments observed in vivo are explained by binding affinities in vitro. Unexpectedly, we found that the highest enriched motif in HOXA2 peaks was not recognised by HOXA2 in vitro, highlighting the importance of investigating HOX binding in its physiological context. We also report the ability of HOXA2 and HOXA3 to heterodimerise, which may have functional consequences for the HOX patterning function in vivo.

Download Full-text

An In-Silico Study on Selected Organosulfur Compounds as Potential Drugs for SARS-CoV-2 Infection via Binding Multiple Drug Targets

10.26434/chemrxiv.12505343 ◽

2020 ◽

Author(s):

Liya Thurakkal ◽

Satyam Singh ◽

Sushabhan Sadhukhan ◽

Mintu Porel

Keyword(s):

Drug Targets ◽

Target Prediction ◽

Multiple Drug ◽

Organosulfur Compounds ◽

Potential Candidate ◽

Health Crisis ◽

Drug Molecules ◽

Main Protease

The emerging paradigm shift from ‘one molecule, one target, for one disease’ towards ‘multi-targeted small molecules’ has paved an ingenious pathway in drug discovery in recent years. This idea has been extracted for the investigation of competent drug molecules for the unprecedented COVID-19 pandemic which became the greatest global health crisis now. Perceiving the importance of organosulfur compounds against SARS-CoV-2 from the drugs under clinical trials, a class of organosulfur compounds effective against SARS-CoV were selected and studied the interaction with multiple proteins of the SARS-CoV-2. One compound displayed inhibition against five proteins (both structural and non-structural) of the virus namely, main protease, papain-like protease, spike protein, helicase and RNA dependent RNA polymerase. Consequently, this compound emanates as a potential candidate for treating the virulent disease. The pharmacokinetics, ADMET properties and target prediction studies carried out in this work further inflamed the versatility of the compound and urge to execute in-vitro and in-vivo analysis on SARS-CoV-2 in the future.

Download Full-text