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Article ; Online: In-silico discovery of dual active molecule to restore synaptic wiring against autism spectrum disorder via HDAC2 and H3R inhibition.

Raja, Anupam / Shekhar, Nishant / Singh, Harvinder / Prakash, Ajay / Medhi, Bikash

2022 Volume 17, Issue 7, Page(s) e0268139

Abstract: Metal-dependent histone deacetylases (HDACs) are essential epigenetic regulators; their molecular and pharmacological roles in medically critical diseases such as neuropsychiatric disorders, neurodegeneration, and cancer are being studied globally. HDAC2' ...

Abstract	Metal-dependent histone deacetylases (HDACs) are essential epigenetic regulators; their molecular and pharmacological roles in medically critical diseases such as neuropsychiatric disorders, neurodegeneration, and cancer are being studied globally. HDAC2's differential expression in the central nervous system makes it an appealing therapeutic target for chronic neurological diseases like autism spectrum disorder. In this study, we identified H3R inhibitor molecules that are computationally effective at binding to the HDAC2 metal-coordinated binding site. The study highlights the importance of pitolisant in screening the potential H3R inhibitors by using a hybrid workflow of ligand and receptor-based drug discovery. The screened lead compounds with PubChem SIDs 103179850, 103185945, and 103362074 show viable binding with HDAC2 in silico. The importance of ligand contacts with the Zn2+ ion in the HDAC2 catalytic site is also discussed and investigated for a significant role in enzyme inhibition. The proposed H3R inhibitors 103179850, 103185945, and 103362074 are estimated as dual-active molecules to block the HDAC2-mediated deacetylation of the EAAT2 gene (SLC1A2) and H3R-mediated synaptic transmission irregularity and are, therefore, open for experimental validation.
MeSH term(s)	Autism Spectrum Disorder/drug therapy ; Autism Spectrum Disorder/genetics ; Histone Deacetylase 2/genetics ; Histone Deacetylase 2/metabolism ; Histone Deacetylase Inhibitors/chemistry ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylases/metabolism ; Humans ; Ligands ; Synaptic Transmission
Chemical Substances	Histone Deacetylase Inhibitors ; Ligands ; HDAC2 protein, human (EC 3.5.1.98) ; Histone Deacetylase 2 (EC 3.5.1.98) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2022-07-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0268139
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Article ; Online: Antiparasitic effect of Farnesol against Leishmania major: A rationale from in vitro and in silico investigations.

Sharma, Harshita / Sehgal, Rakesh / Shekhar, Nishant / Shoeran, Gaurav / Kaur, Upninder / Medhi, Bikash

PloS one

2023 Volume 18, Issue 11, Page(s) e0293290

Abstract: Leishmaniasis is a vector-borne parasitic infection caused by the infective bite of female Phlebotomine sandflies. Treatment of leishmaniasis by conventional synthetic compounds is met by challenges pertaining to adverse effects which call for the ... ...

Abstract	Leishmaniasis is a vector-borne parasitic infection caused by the infective bite of female Phlebotomine sandflies. Treatment of leishmaniasis by conventional synthetic compounds is met by challenges pertaining to adverse effects which call for the discovery of newer anti-leishmanial molecules. This study was performed to evaluate the effect and modes of action of a sesquiterpene alcoholic molecule Farnesol on Leishmania major, the causative agent of Zoonotic CL. The cytotoxic effect of Farnesol against L.major promastigotes, amastigotes and macrophages was assessed by MTT test and counting. The IC50 on promastigotes by Farnesol on L.major was also evaluated by flow cytometry. In the findings, promastigotes were reduced at 167μM. The mean numbers of L.major amastigotes in macrophages were significantly decreased on exposure to Farnesol at 172μM. In addition, Farnesol induced significant apoptosis dose-dependent on L.major promastigotes. In silico protein-ligand_binding analyses indicated the effect of Farnesol in perturbation of the ergosterol synthesis pathway of Leishmania with attributes suggesting inhibition of Lanosterol-α-demethylase, the terminal enzyme of ergosterol synthesis machinery. Findings from flow cytometry reveal the role of Farnesol in apoptosis-induced killing in promastigotes. Farnesol was effective at very lower concentrations when compared to Paromomycin. Further studies are crucial to evaluate the therapeutic potential of Farnesol alone or in combination with other conventional drugs in animal models.
MeSH term(s)	Animals ; Female ; Antiparasitic Agents/pharmacology ; Leishmania major ; Farnesol/pharmacology ; Anti-Infective Agents/pharmacology ; Leishmaniasis/drug therapy ; Ergosterol/pharmacology ; Antiprotozoal Agents/pharmacology
Chemical Substances	Antiparasitic Agents ; Farnesol (4602-84-0) ; Anti-Infective Agents ; Ergosterol (Z30RAY509F) ; Antiprotozoal Agents
Language	English
Publishing date	2023-11-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0293290
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Article ; Online: Indomethacin: an exploratory study of antiviral mechanism and host-pathogen interaction in COVID-19.

Shekhar, Nishant / Kaur, Harpinder / Sarma, Phulen / Prakash, Ajay / Medhi, Bikash

Expert review of anti-infective therapy

2021 Volume 20, Issue 3, Page(s) 383–390

Abstract: Introduction: COVID-19, a dreadful pandemic that has impacted human life like no other pathogenic invasion, has claimed the lives of over 100 million people. The need for effective treatment strategies is still a subject of intense research considering ... ...

Abstract	Introduction: COVID-19, a dreadful pandemic that has impacted human life like no other pathogenic invasion, has claimed the lives of over 100 million people. The need for effective treatment strategies is still a subject of intense research considering the rapidly evolving genome and continental diversity. Indomethacin is administered mostly as co-treatment for affected patients as a non-steroidal anti-inflammatory drug (NSAID). However, the underlying mechanism of action is unresolved. This study explores the basal mechanism of indomethacin and potency in alleviating the damage caused by SARS-CoV-2 and discusses the experimental and clinical efficacy in recent studies. Areas covered: The literature search and system biology-based network formation were employed to describe the potent effects and risks associated with indomethacin in in-vitro, in-vivo, and clinical studies. This study also highlights the plausible mechanism of antiviral action of indomethacin with its apparent viral protein targets. The SARS-CoV-2 protein, the interacting host proteins, and the effect of indomethacin on this interactome as a standalone treatment or as part of a co-therapy strategy are particularly emphasized using network modeling. Expert opinion: Indomethacin has demonstrated excellent clinical endpoint characteristics in several studies, and we recommend that it be utilized in the treatment of mild-to-moderate COVID patients.
MeSH term(s)	Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; Host-Pathogen Interactions ; Humans ; Indomethacin/pharmacology ; Indomethacin/therapeutic use ; SARS-CoV-2/drug effects
Chemical Substances	Antiviral Agents ; Indomethacin (XXE1CET956)
Language	English
Publishing date	2021-10-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2181279-2
ISSN	1744-8336 ; 1478-7210
ISSN (online)	1744-8336
ISSN	1478-7210
DOI	10.1080/14787210.2022.1990756
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Zs.A 6106: Show issues

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Article ; Online: Computational attributes of protein kinase-C gamma C2-domain & virtual screening for small molecules: elucidation from meta-dynamics simulations & free-energy calculations.

Singh, Harvinder / Raja, Anupam / Shekhar, Nishant / Chauhan, Arushi / Prakash, Ajay / Avti, Pramod / Medhi, Bikash

Journal of biomolecular structure & dynamics

2022 Volume 41, Issue 11, Page(s) 4981–4992

Abstract: Epilepsy, a moderate to chronic neuropathological condition, is induced by the acute blockage of synaptic and voltage-gated inhibitory conduction or through the activation of synaptic and voltage-gated excitatory conduction. The regulation of long-term ... ...

Abstract	Epilepsy, a moderate to chronic neuropathological condition, is induced by the acute blockage of synaptic and voltage-gated inhibitory conduction or through the activation of synaptic and voltage-gated excitatory conduction. The regulation of long-term potentiation (LTP) is important in the regulation of epileptic events, and its activity is linked to specific protein kinases. The PKC-γ subtype is a vaguely explored therapeutic target for neurological disorders, but in selected studies, it is proven to be a critical intermediate protein in LTP. This study utilized computational modelling approaches including receptor-based docking, QSAR followed by explicit binding score assessment method MM/GBSA, MM/PBSA (EDA) and MTD simulation-based FES iteration. This was performed to virtually screen the small molecule libraries, which comprised about 2.79 lacs compounds against the Ca
MeSH term(s)	Molecular Dynamics Simulation ; Binding Sites ; Proteins ; Small Molecule Libraries/chemistry ; Molecular Docking Simulation
Chemical Substances	Proteins ; Small Molecule Libraries
Language	English
Publishing date	2022-05-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	49157-3
ISSN	1538-0254 ; 0739-1102
ISSN (online)	1538-0254
ISSN	0739-1102
DOI	10.1080/07391102.2022.2077447
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Zs.A 2093: Show issues

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Article: Ivermectin as a potential drug for treatment of COVID-19: an in-sync review with clinical and computational attributes.

Kaur, Harpinder / Shekhar, Nishant / Sharma, Saurabh / Sarma, Phulen / Prakash, Ajay / Medhi, Bikash

Pharmacological reports : PR

2021 Volume 73, Issue 3, Page(s) 736–749

Abstract: Introduction: COVID-19 cases are on surge; however, there is no efficient treatment or vaccine that can be used for its management. Numerous clinical trials are being reviewed for use of different drugs, biologics, and vaccines in COVID-19. A much ... ...

Abstract	Introduction: COVID-19 cases are on surge; however, there is no efficient treatment or vaccine that can be used for its management. Numerous clinical trials are being reviewed for use of different drugs, biologics, and vaccines in COVID-19. A much empirical approach will be to repurpose existing drugs for which pharmacokinetic and safety data are available, because this will facilitate the process of drug development. The article discusses the evidence available for the use of Ivermectin, an anti-parasitic drug with antiviral properties, in COVID-19. Methods: A rational review of the drugs was carried out utilizing their clinically significant attributes. A more thorough understanding was met by virtual embodiment of the drug structure and realizable viral targets using artificial intelligence (AI)-based and molecular dynamics (MD)-simulation-based study. Conclusion: Certain studies have highlighted the significance of ivermectin in COVID-19; however, it requires evidences from more Randomised Controlled Trials (RCTs) and dose- response studies to support its use. In silico-based analysis of ivermectin's molecular interaction specificity using AI and classical mechanics simulation-based methods indicates positive interaction of ivermectin with viral protein targets, which is leading for SARS-CoV 2 N-protein NTD (nucleocapsid protein N-terminal domain).
MeSH term(s)	Animals ; Antiparasitic Agents/pharmacology ; Antiparasitic Agents/therapeutic use ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; COVID-19/drug therapy ; Humans ; Ivermectin/pharmacology ; Ivermectin/therapeutic use ; Molecular Dynamics Simulation
Chemical Substances	Antiparasitic Agents ; Antiviral Agents ; Ivermectin (70288-86-7)
Language	English
Publishing date	2021-01-03
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2186248-5
ISSN	1734-1140
ISSN	1734-1140
DOI	10.1007/s43440-020-00195-y
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Zs.A 861: Show issues

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Article ; Online: Investigating the novel-binding site of RPA2 on Menin and predicting the effect of point mutation of Menin through protein-protein interactions.

Kaur, Gurjeet / Prajapat, Manisha / Singh, Harvinder / Sarma, Phulen / Bhadada, Sanjay Kumar / Shekhar, Nishant / Sharma, Saurabh / Sinha, Shweta / Kumar, Subodh / Prakash, Ajay / Medhi, Bikash

Scientific reports

2023 Volume 13, Issue 1, Page(s) 9337

Abstract: Protein-protein interactions (PPIs) play a critical role in all biological processes. Menin is tumor suppressor protein, mutated in multiple endocrine neoplasia type 1 syndrome and has been shown to interact with multiple transcription factors including ( ...

Abstract	Protein-protein interactions (PPIs) play a critical role in all biological processes. Menin is tumor suppressor protein, mutated in multiple endocrine neoplasia type 1 syndrome and has been shown to interact with multiple transcription factors including (RPA2) subunit of replication protein A (RPA). RPA2, heterotrimeric protein required for DNA repair, recombination and replication. However, it's still remains unclear the specific amino acid residues that have been involved in Menin-RPA2 interaction. Thus, accurately predicting the specific amino acid involved in interaction and effects of MEN1 mutations on biological systems is of great interests. The experimental approaches for identifying amino acids in menin-RPA2 interactions are expensive, time-consuming, and challenging. This study leverages computational tools, free energy decomposition and configurational entropy scheme to annotate the menin-RPA2 interaction and effect on menin point mutation, thereby proposing a viable model of menin-RPA2 interaction. The menin-RPA2 interaction pattern was calculated on the basis of different 3D structures of menin and RPA2 complexes, constructed using homology modeling and docking strategy, generating three best-fit models: Model 8 (- 74.89 kJ/mol), Model 28 (- 92.04 kJ/mol) and Model 9 (- 100.4 kJ/mol). The molecular dynamic (MD) was performed for 200 ns and binding free energies and energy decomposition analysis were calculated using Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) in GROMACS. From binding free energy change, model 8 of Menin-RPA2 exhibited most negative binding energy of - 205.624 kJ/mol, followed by model 28 of Menin-RPA2 with - 177.382 kJ/mol. After S606F point mutation in Menin, increase of BFE (ΔG
MeSH term(s)	Humans ; Point Mutation ; Mutation ; Transcription Factors/genetics ; Binding Sites ; Multiple Endocrine Neoplasia Type 1 ; Amino Acids/genetics ; Replication Protein A/genetics
Chemical Substances	Transcription Factors ; Amino Acids ; RPA2 protein, human (EC 2.7.7.7) ; Replication Protein A
Language	English
Publishing date	2023-06-08
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/s41598-023-35599-2
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Article ; Online: Structural and conformational analysis of SARS CoV 2 N-CTD revealing monomeric and dimeric active sites during the RNA-binding and stabilization: Insights towards potential inhibitors for N-CTD.

Chauhan, Arushi / Avti, Pramod / Shekhar, Nishant / Prajapat, Manisha / Sarma, Phulen / Bhattacharyya, Anusuya / Kumar, Subodh / Kaur, Hardeep / Prakash, Ajay / Medhi, Bikash

Computers in biology and medicine

2021 Volume 134, Page(s) 104495

Abstract: The advent of SARS-CoV-2 has become a universal health issue with no appropriate cure available to date. The coronavirus nucleocapsid (N) protein combines viral genomic RNA into a ribonucleoprotein and protects the viral genome from the host's nucleases. ...

Abstract	The advent of SARS-CoV-2 has become a universal health issue with no appropriate cure available to date. The coronavirus nucleocapsid (N) protein combines viral genomic RNA into a ribonucleoprotein and protects the viral genome from the host's nucleases. Structurally, the N protein comprises two independent domains: the N-terminal domain (NTD) for RNA-binding and C-terminal domain (CTD) involved in RNA-binding, protein dimerization, and nucleocapsid stabilization. The present study explains the structural aspects associated with the involvement of nucleocapsid C-terminal domain in the subunit assembly that helps the RNA binding and further stabilizing the virus assembly by protecting RNA from the hosts exonucleases degradation. The molecular dynamics (MD) simulations of the N-CTD and RNA complex suggests two active sites (site I: a monomer) and (site II: a dimer) with structural stability (RMSD: ~2 Å), Cα fluctuations (RMSF: ~3 Å) and strong protein-ligand interactions were estimated through the SiteMap module of Schrodinger. Virtual screening of 2456 FDA-approved drugs using structure-based docking identified top two leads distinctively against Site-I (monomer): Ceftaroline fosamil (MM-GBSA = -47.12 kcal/mol) and Cefoperazone (-45.84 kcal/mol); and against Site-II (dimer): Boceprevir, (an antiviral protease inhibitor, -106.78 kcal/mol) and Ceftaroline fosamil (-99.55 kcal/mol). The DCCM and PCA of drugs Ceftaroline fosamil (PC1+PC2 = 71.9%) and Boceprevir (PC1 +PC2 = 61.6%) show significant correlated residue motions which suggests highly induced conformational changes in the N-CTD dimer. Therefore, we propose N-CTD as a druggable target with two active binding sites (monomer and dimer) involved in specific RNA binding and stability. The RNA binding site with Ceftaroline fosamil binding can prevent viral assembly and can act as an antiviral for coronavirus.
Language	English
Publishing date	2021-05-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	127557-4
ISSN	1879-0534 ; 0010-4825
ISSN (online)	1879-0534
ISSN	0010-4825
DOI	10.1016/j.compbiomed.2021.104495
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Zs.A 653: Show issues

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Article ; Online: Multi-epitope based peptide vaccine design against SARS-CoV-2 using its spike protein

Mitra, Debarghya / Shekhar, Nishant / Pandey, Janmejay / Jain, Alok / Swaroop, Shiv

bioRxiv

Abstract: SARS CoV-2 has particularly been efficient in ensuring that entire countries are brought to a standstill. With repercussions ranging from rampant mortality, fear, paranoia and economic recession the virus has brought together countries in order to look ... ...

Abstract	SARS CoV-2 has particularly been efficient in ensuring that entire countries are brought to a standstill. With repercussions ranging from rampant mortality, fear, paranoia and economic recession the virus has brought together countries in order to look at possible therapeutic countermeasures. With prophylactic interventions possibly months away from particularly being effective, a slew of measures and possibilities concerning design of vaccines are being worked upon. We attempt a structure based approach utilizing a combination of epitope prediction servers to develop a multi-epitope based subunit vaccine that involves the two major domains of the spike glycoprotein of SARS CoV-2 ( S1 and S2) coupled with a substantially effective chimeric adjuvant acting as a triagonist to substantially create stable vaccine constructs through MD simulations. The designed constructs are evaluated based on their docking with Toll Like Receptor (TLR) 4. Our findings provide epitope-based peptide fragment which can be potential candidates for development of vaccine against SARS-CoV-2.
Keywords	covid19
Language	English
Publishing date	2020-04-24
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2020.04.23.055467
Database	COVID19

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Article ; Online: Multi-epitope based peptide vaccine design against SARS-CoV-2 using its spike protein

Mitra, Debarghya / Shekhar, Nishant / Pandey, Janmejay / Jain, Alok / Swaroop, Shiv

bioRxiv

Abstract	SARS CoV-2 has particularly been efficient in ensuring that entire countries are brought to a standstill. With repercussions ranging from rampant mortality, fear, paranoia and economic recession the virus has brought together countries in order to look at possible therapeutic countermeasures. With prophylactic interventions possibly months away from particularly being effective, a slew of measures and possibilities concerning design of vaccines are being worked upon. We attempt a structure based approach utilizing a combination of epitope prediction servers to develop a multi-epitope based subunit vaccine that involves the two major domains of the spike glycoprotein of SARS CoV-2 (S1 and S2) coupled with a substantially effective chimeric adjuvant to create stable vaccine constructs through MD simulations. The designed constructs are evaluated based on their docking with Toll Like Receptor (TLR) 4. Our findings provide epitope-based peptide fragment which can be potential candidate for development of vaccine against SARS-CoV-2. Recent experimental studies based on determining immunodominant regions across the spike glycoprotein of SARS-CoV-2 indicate the presence of the predicted epitopes included in this study.
Keywords	covid19
Publisher	BioRxiv
Document type	Article ; Online
DOI	10.1101/2020.04.23.055467
Database	COVID19

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Article ; Online: Virtual screening and molecular dynamics simulation study of approved drugs as a binder to the linoleic acid binding site on spike protein of SARS-CoV-2 and double mutant (E484Q and L452R).

Prajapat, Manisha / Sarma, Phulen / Shekhar, Nishant / Chauhan, Arushi / Kaur, Gurjeet / Bhattacharyya, Anusuya / Avti, Pramod / Choudhary, Gajendra / Bansal, Seema / Sharma, Saurabh / Kaur, Hardeep / Kumar, Subodh / Mann, Harvinder / Raja, Anupam / Singh, Ashutosh / Singh, Rahul / Sharma, Amit Raj / Prakash, Ajay / Medhi, Bikash

Indian journal of pharmacology

2023 Volume 54, Issue 6, Page(s) 431–442

Abstract: Introduction: Binding of linoleic acid (LA) to the spike trimer stabilizes it in closed conformation hindering its binding to angiotensin-converting enzyme-2, thus decreasing infectivity. In the current study, we tend to repurpose Food and Drug ... ...

Abstract	Introduction: Binding of linoleic acid (LA) to the spike trimer stabilizes it in closed conformation hindering its binding to angiotensin-converting enzyme-2, thus decreasing infectivity. In the current study, we tend to repurpose Food and Drug Administration-approved drugs as binder to the LA binding pocket in wild and double mutant spike protein. Materials and methods: Approved drugs from DrugBank database (n = 2456) were prepared using Ligprep module of Schrodinger. Crystal structure of LA bound to spike trimer was retrieved (PDB: 6ZB4) and prepared using protein preparation wizard and grid was generated. A virtual screening was performed. With the help of molecular dynamics (MD) studies interaction profile of screened drugs were further evaluated. The selected hits were further evaluated for binding to the double mutant form of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Results and discussion: Following virtual screening, a total of 26 molecules were shortlisted, which were further evaluated using 1ns MD simulation study. Four ligands showing better root mean square deviation (RMSD), RMSD to LA with interaction profile similar to LA were further evaluated using 100 ns MD simulation studies. A total of 2 hits were identified, which performed better than LA (selexipag and pralatrexate). Both these ligands were also found to bind to LA binding site of the double mutant form (E484Q and L452R); however, the binding affinity of pralatrexate was found to be better. Conclusion: We have identified 2 ligands (selexipag and pralatrexate) as possible stable binders to the LA binding site in spike trimer (wild and mutant form). Among them, pralatrexate has shown in vitro activity against SARS-CoV-2, validating our study results.
MeSH term(s)	Binding Sites ; Ligands ; Linoleic Acid ; Molecular Dynamics Simulation ; SARS-CoV-2/drug effects ; SARS-CoV-2/genetics ; Spike Glycoprotein, Coronavirus/genetics ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology
Chemical Substances	Ligands ; Linoleic Acid (9KJL21T0QJ) ; selexipag (5EXC0E384L) ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; Antiviral Agents
Language	English
Publishing date	2023-02-20
Publishing country	India
Document type	Journal Article
ZDB-ID	605829-2
ISSN	1998-3751 ; 0253-7613
ISSN (online)	1998-3751
ISSN	0253-7613
DOI	10.4103/ijp.ijp_111_22
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