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  1. Article ; Online: Pinpointing top inhibitors for GSK3β from pool of indirubin derivatives using rigorous computational workflow and their validation using molecular dynamics (MD) simulations

    Vamangi Pandya / Priyashi Rao / Jignesh Prajapati / Rakesh M. Rawal / Dweipayan Goswami

    Scientific Reports, Vol 14, Iss 1, Pp 1-

    2024  Volume 25

    Abstract: Abstract Glycogen synthase kinase-3β (GSK3β) is a pivotal protein kinase implicated in a spectrum of debilitating diseases, encompassing cancer, diabetes, and neurodegenerative disorders. While the therapeutic potential of GSK3β inhibition is widely ... ...

    Abstract Abstract Glycogen synthase kinase-3β (GSK3β) is a pivotal protein kinase implicated in a spectrum of debilitating diseases, encompassing cancer, diabetes, and neurodegenerative disorders. While the therapeutic potential of GSK3β inhibition is widely recognized, there remains an unmet need for a rigorous, systematic analysis probing the theoretical inhibition dynamics of a comprehensive library of indirubin derivatives against GSK3β using advanced computational methodologies. Addressing this gap, this study embarked on an ambitious endeavor, leveraging indirubin—a renowned scaffold—as a template to curate a vast library of 1000 indirubin derivatives from PubChem. These were enriched with varied substitutions and modifications, identified via a structure similarity search with a Tanimoto similarity threshold of 85%. Harnessing a robust virtual screening workflow, we meticulously identified the top 10 contenders based on XP docking scores. Delving deeper, we gauged the binding free energy differentials (ΔGBind) of these hits, spotlighting the top three compounds that showcased unparalleled binding prowess. A comparative pharmacophore feature mapping with the reference inhibitor OH8, co-crystallized with GSK3β (PDB ID: 6Y9R), was undertaken. The binding dynamics of these elite compounds were further corroborated with 100 ns molecular dynamics simulations, underlining their stable and potent interactions with GSK3β. Remarkably, our findings unveil that these indirubin derivatives not only match but, in certain scenarios, surpass the binding affinity and specificity of OH8. By bridging this research chasm, our study amplifies the therapeutic promise of indirubin derivatives, positioning them as frontrunners in the quest for groundbreaking GSK3β inhibitors, potentially revolutionizing treatments for a myriad of ailments.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Pinpointing top inhibitors for GSK3β from pool of indirubin derivatives using rigorous computational workflow and their validation using molecular dynamics (MD) simulations.

    Pandya, Vamangi / Rao, Priyashi / Prajapati, Jignesh / Rawal, Rakesh M / Goswami, Dweipayan

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 49

    Abstract: Glycogen synthase kinase-3β (GSK3β) is a pivotal protein kinase implicated in a spectrum of debilitating diseases, encompassing cancer, diabetes, and neurodegenerative disorders. While the therapeutic potential of GSK3β inhibition is widely recognized, ... ...

    Abstract Glycogen synthase kinase-3β (GSK3β) is a pivotal protein kinase implicated in a spectrum of debilitating diseases, encompassing cancer, diabetes, and neurodegenerative disorders. While the therapeutic potential of GSK3β inhibition is widely recognized, there remains an unmet need for a rigorous, systematic analysis probing the theoretical inhibition dynamics of a comprehensive library of indirubin derivatives against GSK3β using advanced computational methodologies. Addressing this gap, this study embarked on an ambitious endeavor, leveraging indirubin-a renowned scaffold-as a template to curate a vast library of 1000 indirubin derivatives from PubChem. These were enriched with varied substitutions and modifications, identified via a structure similarity search with a Tanimoto similarity threshold of 85%. Harnessing a robust virtual screening workflow, we meticulously identified the top 10 contenders based on XP docking scores. Delving deeper, we gauged the binding free energy differentials (ΔGBind) of these hits, spotlighting the top three compounds that showcased unparalleled binding prowess. A comparative pharmacophore feature mapping with the reference inhibitor OH8, co-crystallized with GSK3β (PDB ID: 6Y9R), was undertaken. The binding dynamics of these elite compounds were further corroborated with 100 ns molecular dynamics simulations, underlining their stable and potent interactions with GSK3β. Remarkably, our findings unveil that these indirubin derivatives not only match but, in certain scenarios, surpass the binding affinity and specificity of OH8. By bridging this research chasm, our study amplifies the therapeutic promise of indirubin derivatives, positioning them as frontrunners in the quest for groundbreaking GSK3β inhibitors, potentially revolutionizing treatments for a myriad of ailments.
    MeSH term(s) Molecular Dynamics Simulation ; Glycogen Synthase Kinase 3 beta ; Workflow ; Indoles/pharmacology ; Molecular Docking Simulation
    Chemical Substances Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; indirubin (V86L8P74GI) ; Indoles
    Language English
    Publishing date 2024-01-02
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-50992-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Extending the lore of curcumin as dipteran Butyrylcholine esterase (BChE) inhibitor

    Priyashi Rao / Dweipayan Goswami / Rakesh M Rawal

    PLoS ONE, Vol 17, Iss 5, p e

    A holistic molecular interplay assessment.

    2022  Volume 0269036

    Abstract: Since its origin, the emergence of vector-borne infections has taken a toll on incalculable human lives. The use of chemical insecticides is one of the early known methods of vector control and although their use is still a prevalent way to combat insect ...

    Abstract Since its origin, the emergence of vector-borne infections has taken a toll on incalculable human lives. The use of chemical insecticides is one of the early known methods of vector control and although their use is still a prevalent way to combat insect population sadly the perils of insects related transmission still persists. Most commonly, the existing insecticides face the wrath of getting resisted repeatedly, paying way to develop resilient, efficient, and cost-effective natural insecticides. In this study, computational screening was performed using homology modelling, E-pharmacophore feature mapping, molecular docking, Density Function Theory (DFT) assessment, Molecular mechanics generalized Born surface area (MM-GBSA) based binding free energy calculations and Molecular Dynamics (MD) simulation to identify a potential lead phytochemical out of a manually curated library from published literature. The protein target used under this study is insect Butyrylcholine esterase (BChE). Additionally, in vitro insect (Aedes aegypti) BChE inhibition assay was also performed with the top phytochemical identified from in silico assessments. Our research highlights that curcumin leads to inhibition of enzyme BChE of Ae. aegypti. The identified mode of action of curcumin as an insect BChE inhibitor indicates the possibility of its use as an environment friendly and natural futuristic insecticide.
    Keywords Medicine ; R ; Science ; Q
    Subject code 541
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Extending the lore of curcumin as dipteran Butyrylcholine esterase (BChE) inhibitor: A holistic molecular interplay assessment.

    Rao, Priyashi / Goswami, Dweipayan / Rawal, Rakesh M

    PloS one

    2022  Volume 17, Issue 5, Page(s) e0269036

    Abstract: Since its origin, the emergence of vector-borne infections has taken a toll on incalculable human lives. The use of chemical insecticides is one of the early known methods of vector control and although their use is still a prevalent way to combat insect ...

    Abstract Since its origin, the emergence of vector-borne infections has taken a toll on incalculable human lives. The use of chemical insecticides is one of the early known methods of vector control and although their use is still a prevalent way to combat insect population sadly the perils of insects related transmission still persists. Most commonly, the existing insecticides face the wrath of getting resisted repeatedly, paying way to develop resilient, efficient, and cost-effective natural insecticides. In this study, computational screening was performed using homology modelling, E-pharmacophore feature mapping, molecular docking, Density Function Theory (DFT) assessment, Molecular mechanics generalized Born surface area (MM-GBSA) based binding free energy calculations and Molecular Dynamics (MD) simulation to identify a potential lead phytochemical out of a manually curated library from published literature. The protein target used under this study is insect Butyrylcholine esterase (BChE). Additionally, in vitro insect (Aedes aegypti) BChE inhibition assay was also performed with the top phytochemical identified from in silico assessments. Our research highlights that curcumin leads to inhibition of enzyme BChE of Ae. aegypti. The identified mode of action of curcumin as an insect BChE inhibitor indicates the possibility of its use as an environment friendly and natural futuristic insecticide.
    MeSH term(s) Aedes ; Animals ; Choline/analogs & derivatives ; Cholinesterases/metabolism ; Curcumin/metabolism ; Curcumin/pharmacology ; Enzyme Inhibitors/pharmacology ; Humans ; Insecticide Resistance ; Insecticides/metabolism ; Insecticides/pharmacology ; Molecular Docking Simulation ; Mosquito Vectors/metabolism
    Chemical Substances Enzyme Inhibitors ; Insecticides ; butyrylcholine (3922-86-9) ; Cholinesterases (EC 3.1.1.8) ; Curcumin (IT942ZTH98) ; Choline (N91BDP6H0X)
    Language English
    Publishing date 2022-05-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0269036
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Molecular insights on ar-turmerone as a structural, functional and pharmacophoric analogue of synthetic mosquito repellent DEET by comprehensive computational assessment.

    Rao, Priyashi / Goswami, Dweipayan / Rawal, Rakesh M

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 15564

    Abstract: Mosquitoes are vectors for a variety of infectious illnesses, and chemical synthetic insecticides have made it possible to control them effectively. Mosquito repellents are a typical means of keeping mosquitos at bay. Because of its main effectiveness of ...

    Abstract Mosquitoes are vectors for a variety of infectious illnesses, and chemical synthetic insecticides have made it possible to control them effectively. Mosquito repellents are a typical means of keeping mosquitos at bay. Because of its main effectiveness of skin permeability, N,N-Diethyl-meta-toluamide (DEET) is one of the most extensively used mosquito repellents but a dangerous synthetic chemical. DEET was identified about a decade ago to inhibit mosquito's Odorant Binding Protein 1 (OBP1), impairing the mosquito's ability to recognise the host body odour. OBP1 has been identified as a possible target for the development of new mosquito repellents since its discovery. Essential oils from different plants, on the other hand, have been used to repel mosquitos since antiquity. One essential oil from the Curcuma longa (Zingiberales: Zingiberaceae) rhizome display mosquito repellent properties, according to the literature. Furthermore, one of the phytochemicals found in abundance in C. longa essential oil, ar-turmerone, exhibits mosquito repellency as comparable to synthetic DEET. Till date studies on in-silico interaction of natural ar-turmerone with OBP1, which we depict in our current work are scarce. Further, there exist no published reports demonstrating the literary evidence on detailed insights of interaction of DEET with OBP1 along with Molecular Dynamics (MD) simulation studies. We further performed detailed molecular investigations using pharmacophore analysis of ar-turmerone and compared it with DEET, where our findings in the current manuscript unveils for the first time that ar-turmerone is a functional, structural and pharmacophoric analogue of DEET.
    MeSH term(s) Animals ; DEET/pharmacology ; Insect Repellents/chemistry ; Insect Repellents/pharmacology ; Insecticides ; Ketones ; Oils, Volatile/chemistry ; Oils, Volatile/pharmacology ; Sesquiterpenes
    Chemical Substances Insect Repellents ; Insecticides ; Ketones ; Oils, Volatile ; Sesquiterpenes ; DEET (134-62-3) ; ar-turmerone (1944T899NO)
    Language English
    Publishing date 2022-09-16
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-19901-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Revealing the molecular interplay of curcumin as Culex pipiens Acetylcholine esterase 1 (AChE1) inhibitor

    Priyashi Rao / Dweipayan Goswami / Rakesh M. Rawal

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 18

    Abstract: Abstract Emergence of vector borne diseases has continued to take toll on millions of lives since its inception. The use of insecticides began as vector control strategy in the early 1900’s but the menace of insects is still prevalent. Additionally, the ... ...

    Abstract Abstract Emergence of vector borne diseases has continued to take toll on millions of lives since its inception. The use of insecticides began as vector control strategy in the early 1900’s but the menace of insects is still prevalent. Additionally, the inadequate use of organophosphates and carbamates which target acetylcholine esterase (AChE), are known to develop resistance amongst vectors of transmission and are toxic to humans. In this study, extensive computational screening was performed using homology modelling, molecular docking, molecular dynamics (MD) simulation and free energy change calculation, which highlighted curcumin as a lead molecule out of ~ 1700 phytochemicals against Culex pipiens AChE. In vivo larvicidal activity was carried out along with in vivo and in vitro AChE inhibition assay to determine the biochemical efficacy of curcumin. Our study reveals that curcumin induces mortality in Cx. pipiens at an early stage of its life cycle by AChE inhibition. This also underlines the use of curcumin as a coming-age natural product insecticide.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Curcumin interferes with chitin synthesis in Aedes aegypti: a computational and experimental investigation.

    Rao, Priyashi / Ninama, Jinal / Dudhat, Mansi / Goswami, Dweipayan / Rawal, Rakesh M

    Molecular diversity

    2023  

    Abstract: Throughout history, vector-borne diseases have consistently posed significant challenges to human health. Among the strategies for vector control, chemical insecticides have seen widespread use since their inception. Nevertheless, their effectiveness is ... ...

    Abstract Throughout history, vector-borne diseases have consistently posed significant challenges to human health. Among the strategies for vector control, chemical insecticides have seen widespread use since their inception. Nevertheless, their effectiveness is continually undermined by the steady growth of insecticide resistance within these vector populations. As such, the demand for more robust, efficient, and cost-effective natural insecticides has become increasingly pressing. One promising avenue of research focuses on chitin, a crucial structural component of mosquitoes' exoskeletons and other insects. Chitin not only provides protection and rigidity but also lends flexibility to the insect body. It undergoes substantial transformations during insect molting, a process known as ecdysis. Crucially, the production of chitin is facilitated by an enzyme known as chitin synthase, making it an attractive target for potential novel insecticides. Our recent study delved into the impacts of curcumin, a natural derivative of turmeric, on chitin synthesis and larval development in Aedes aegypti, a mosquito species known to transmit dengue and yellow fever. Our findings demonstrate that even sub-lethal amounts of curcumin can significantly reduce overall chitin content and disrupt the cuticle development in the 4th instar larvae of Aedes aegypti. Further to this, we utilized computational analyses to investigate how curcumin interacts with chitin synthase. Techniques such as molecular docking, pharmacophore feature mapping, and molecular dynamics (MD) simulations helped to illustrate that curcumin binds to the same site as polyoxin D, a recognized inhibitor of chitin synthase. These findings point to curcumin's potential as a natural, bioactive larvicide that targets chitin synthase in mosquitoes and potentially other insects.
    Language English
    Publishing date 2023-06-26
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 1376507-3
    ISSN 1573-501X ; 1381-1991
    ISSN (online) 1573-501X
    ISSN 1381-1991
    DOI 10.1007/s11030-023-10672-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Revealing the molecular interplay of curcumin as Culex pipiens Acetylcholine esterase 1 (AChE1) inhibitor.

    Rao, Priyashi / Goswami, Dweipayan / Rawal, Rakesh M

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 17474

    Abstract: Emergence of vector borne diseases has continued to take toll on millions of lives since its inception. The use of insecticides began as vector control strategy in the early 1900's but the menace of insects is still prevalent. Additionally, the ... ...

    Abstract Emergence of vector borne diseases has continued to take toll on millions of lives since its inception. The use of insecticides began as vector control strategy in the early 1900's but the menace of insects is still prevalent. Additionally, the inadequate use of organophosphates and carbamates which target acetylcholine esterase (AChE), are known to develop resistance amongst vectors of transmission and are toxic to humans. In this study, extensive computational screening was performed using homology modelling, molecular docking, molecular dynamics (MD) simulation and free energy change calculation, which highlighted curcumin as a lead molecule out of ~ 1700 phytochemicals against Culex pipiens AChE. In vivo larvicidal activity was carried out along with in vivo and in vitro AChE inhibition assay to determine the biochemical efficacy of curcumin. Our study reveals that curcumin induces mortality in Cx. pipiens at an early stage of its life cycle by AChE inhibition. This also underlines the use of curcumin as a coming-age natural product insecticide.
    MeSH term(s) Acetylcholine/metabolism ; Acetylcholinesterase/chemistry ; Amino Acid Sequence ; Animals ; Cholinesterase Inhibitors/pharmacology ; Culex/enzymology ; Curcumin/pharmacology ; Molecular Docking Simulation ; Protein Conformation ; Sequence Homology
    Chemical Substances Cholinesterase Inhibitors ; Acetylcholinesterase (EC 3.1.1.7) ; Curcumin (IT942ZTH98) ; Acetylcholine (N9YNS0M02X)
    Language English
    Publishing date 2021-09-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-96963-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Identification of hub genes associated with prognosis of lung cancer via integrated bioinformatics and

    Yadav, Deep Kumari / Bhadresha, Kinjal / Rao, Priyashi / Shaikh, Shayma / Rawal, Rakesh M

    Journal of biomolecular structure & dynamics

    2022  Volume 41, Issue 20, Page(s) 11204–11218

    Abstract: Lung cancer is a severe health problem that affects more men than women around the world. The goal of this study was to identify the biomarker hub genes for lung cancer in order to ascertain the biological pathway and protein- protein interaction ... ...

    Abstract Lung cancer is a severe health problem that affects more men than women around the world. The goal of this study was to identify the biomarker hub genes for lung cancer in order to ascertain the biological pathway and protein- protein interaction networks. The microarray datasets GSE80796, GSE68571, GSE118370 and GSE43458 were retrieved from the GEO database and were analysed using GEO2R. STRING, Cytoscape, and cytoHubba were used to construct the PPI network and hub genes. GEPIA was used to obtain the overall survival and expression level in LUAD/LUSC and normal tissue. The MTT assay was used to examine antiproliferative activity. PI staining was used to determine the cell cycle arrest. qPCR was used to analyse gene expressions. The datasets revealed a total of 401 common DEGs, with 258 up-regulated genes and 143 down-regulated genes. Further,
    MeSH term(s) Male ; Female ; Humans ; Lung Neoplasms/genetics ; Gene Expression Profiling ; Biomarkers, Tumor/genetics ; Computational Biology ; Gallic Acid ; Gene Expression Regulation, Neoplastic
    Chemical Substances Biomarkers, Tumor ; Gallic Acid (632XD903SP)
    Language English
    Publishing date 2022-12-26
    Publishing country England
    Document type Journal Article
    ZDB-ID 49157-3
    ISSN 1538-0254 ; 0739-1102
    ISSN (online) 1538-0254
    ISSN 0739-1102
    DOI 10.1080/07391102.2022.2160816
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: A Comprehensive in vitro and in silico Assessment on Inhibition of CYP51B and Ergosterol Biosynthesis by Eugenol in Rhizopus oryzae

    Prajapati, Jignesh / Rao, Priyashi / Poojara, Lipi / Acharya, Dhaval / Patel, Saumya K. / Goswami, Dweipayan / Rawal, Rakesh M.

    Curr Microbiol. 2023 Jan., v. 80, no. 1 p.47-47

    2023  

    Abstract: Mucormycosis, also known as Zygomycosis, is a disease caused by invasive fungi, predominantly Rhizopus species belonging to the Order of Mucorales. Seeing from the chemistry perspective, heterocyclic compounds with an "azole" moiety are widely employed ... ...

    Abstract Mucormycosis, also known as Zygomycosis, is a disease caused by invasive fungi, predominantly Rhizopus species belonging to the Order of Mucorales. Seeing from the chemistry perspective, heterocyclic compounds with an "azole" moiety are widely employed as antifungal agent for minimising the effect of mucormycosis as a prescribed treatment. These azoles serve as non-competitive inhibitors of fungal CYP51B by predominantly binding to its heme moiety, rendering its inhibition. However, long-term usage and abuse of azoles as antifungal medicines has resulted in drug resistance among certain fungal pathogens. Hence, there is an unmet need to find alternative therapeutic compounds. In present study, we used various in vitro tests to investigate the antifungal activity of eugenol against R. oryzae/R. arrhizus, including ergosterol quantification to test inhibition of ergosterol production mediated antifungal action. The minimum inhibitory concentration (MIC) value obtained for eugenol was 512 μg/ml with reduced ergosterol concentration of 77.11 ± 3.25% at MIC/2 concentration. Further, the molecular interactions of eugenol with fungal CYP51B were meticulously studied making use of proteomics in silico study including molecular docking and molecular dynamics simulations that showed eugenol to be strongly interacting with heme in an identical fashion to that shown by azole drugs (in this case, clotrimazole was evaluated). This is the first of a kind study showing the simulation study of eugenol with CYP51B of fungi. This inhibition results in ergosterol synthesis and is also studied and compared with keeping clotrimazole as a reference.
    Keywords Rhizopus oryzae ; antifungal properties ; biosynthesis ; clotrimazole ; computer simulation ; drug resistance ; ergosterol ; eugenol ; fungi ; heme ; minimum inhibitory concentration ; moieties ; molecular dynamics ; proteomics ; therapeutics ; zygomycosis
    Language English
    Dates of publication 2023-01
    Size p. 47.
    Publishing place Springer US
    Document type Article ; Online
    ZDB-ID 134238-1
    ISSN 1432-0991 ; 0343-8651
    ISSN (online) 1432-0991
    ISSN 0343-8651
    DOI 10.1007/s00284-022-03108-9
    Database NAL-Catalogue (AGRICOLA)

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