scholarly journals Computational designing of a peptide that potentially blocks the entry of SARS-CoV, SARS-CoV-2 and MERS-CoV

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0251913
Author(s):  
Priya V. K. ◽  
Satish Prasad Rath ◽  
Parvin Abraham
Keyword(s):  
Docking Studies ◽  
Peptide Inhibitor ◽  
Receptor Interaction ◽  
Stable Complex ◽  
Potential Candidate ◽  
Virus Infections ◽  
Dynamic Simulations ◽  
Viral Receptor ◽  
Viral Therapy ◽  
Consensus Peptide

Last decade has witnessed three major pandemics caused by SARS-CoV, SARS-CoV-2 and MERS-CoV that belong to Coronavirus family. Currently, there are no effective therapies available for corona virus infections. Since the three viruses belong to the same family and share many common features, we can theoretically design a drug that can be effective on all the three of them. In this study, using computational approach, we designed a peptide (Peptide 7) that can bind to the Receptor Binding Domain (RBD) of SARS-CoV, SARS-CoV-2 and MERS-CoV thereby preventing the entry of the viruses into the host cell. The peptide inhibitor was designed as a consensus peptide from three different peptides that might individually bind to the RBD of the three viruses. Docking studies and molecular dynamic simulations using Peptide 7 has shown that it binds with higher affinity than the native receptors of the RBD and forms a stable complex thereby preventing further viral-receptor interaction and inhibiting their cellular entry. This effective binding is observed for the three RBDs, despite the Peptide 7 interactions being slightly different. Hence; this peptide inhibitor can be used as a potential candidate for the development of peptide based anti-viral therapy against Corona viruses.

Design and synthesis of new antifungals based on N- un-substituted azoles as 14α demethylase inhibitor

2020 ◽  
Vol 16 ◽  
Author(s):  
Asghar Davood ◽  
Aneseh Rahimi ◽  
Maryam Iman ◽  
Parisa Azerang ◽  
Soroush Sardari ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Antifungal Agents ◽  
Molecular Design ◽  
Pathogenic Fungi ◽  
Antimicrobial Activities ◽  
Docking Studies ◽  
Receptor Interaction ◽  
Main Role ◽  
Design And Synthesis ◽  
Antifungal Antibiotics

Objective(s): Azole antifungal agents, which are widely used as antifungal antibiotics, inhibit cytochrome P450 sterol 14α-demethylase (CYP51). Nearly all azole antifungal agents are N-substituted azoles. In addition, an azolylphenalkyl pharmacophore is uniquely shared by all azole antifungals. Due to importance of nitrogen atom of azoles (N-3 of imidazole and N-4 of triazole) in coordination with heme in the binding site of the enzyme, here a group of N- un-substituted azoles in which both of nitrogen is un-substituted was reported. Materials and Methods: Designed compounds were synthesized by reaction of imidazole-4-carboxaldehyde with appropriate arylamines and subsequently reduced to desired amine derivatives. Antifungal activity against Candida albicans and Saccharomyces cervisiae were done using a broth micro-dilution assay. Docking studies were done using AutoDock. Results: Antimicrobial evaluation revealed that some of these compounds exhibited moderate antimicrobial activities against tested pathogenic fungi, wherein compound 3, 7 and 8 were potent. Docking studies propose that all of the prepared azoles interacted with 14α-DM, wherein azole-heme coordination play main role in drug-receptor interaction. Conclusion: Our results offer some useful references in order to molecular design performance or modification of this series of compounds as a lead compound to discover new and potent antimicrobial agents.

Elucidating the anti-biofilm and anti-quorum sensing potential of selenocystine against respiratory tract infections causing bacteria: in vitro and in silico studies

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Bharti Patel ◽  
Subrata Mishra ◽  
Indira K. Priyadarsini ◽  
Sirisha L. Vavilala
Keyword(s):  
Quorum Sensing ◽  
Respiratory Tract ◽  
Protein Function ◽  
Docking Studies ◽  
Klebsiella Pneumonia ◽  
Potential Candidate ◽  
In Silico Studies ◽  
Specific Proteins ◽  
Tract Infections

Abstract Bacteria are increasingly relying on biofilms to develop resistance to antibiotics thereby resulting in their failure in treating many infections. In spite of continuous research on many synthetic and natural compounds, ideal anti-biofilm molecule is still not found thereby warranting search for new class of molecules. The current study focuses on exploring anti-biofilm potential of selenocystine against respiratory tract infection (RTI)-causing bacteria. Anti-bacterial and anti-biofilm assays demonstrated that selenocystine inhibits the growth of bacteria in their planktonic state, and formation of biofilms while eradicating preformed-biofilm effectively. Selenocystine at a MIC50 as low as 42 and 28 μg/mL effectively inhibited the growth of Klebsiella pneumonia and Pseudomonas aeruginosa. The antibacterial effect is further reconfirmed by agar cup diffusion assay and growth-kill assay. Selenocystine showed 30–60% inhibition of biofilm formation in K. pneumonia, and 44–70% in P. aeruginosa respectively. It also distorted the preformed-biofilms by degrading the eDNA component of the Extracellular Polymeric Substance matrix. Molecular docking studies of selenocystine with quorum sensing specific proteins clearly showed that through the carboxylic acid moiety it interacts and inhibits the protein function, thereby confirming its anti-biofilm potential. With further validation selenocystine can be explored as a potential candidate for the treatment of RTIs.

scholarly journals The Odd Faces of Oligomers: The Case of TRAF2-C, A Trimeric C-Terminal Domain of TNF Receptor-Associated Factor

2021 ◽  
Vol 22 (11) ◽  
pp. 5871
Author(s):  
Almerinda Di Venere ◽  
Eleonora Nicolai ◽  
Velia Minicozzi ◽  
Anna Maria Caccuri ◽  
Luisa Di Paola ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Strong Dependence ◽  
Conformational Dynamics ◽  
Receptor Interaction ◽  
Tnf Receptor ◽  
Oligomeric State ◽  
Dynamic Simulations ◽  
Associated Factor ◽  
Terminal Domain

TNF Receptor Associated Factor 2 (TRAF2) is a trimeric protein that belongs to the TNF receptor associated factor family (TRAFs). The TRAF2 oligomeric state is crucial for receptor binding and for its interaction with other proteins involved in the TNFR signaling. The monomer-trimer equilibrium of a C- terminal domain truncated form of TRAF2 (TRAF2-C), plays also a relevant role in binding the membrane, causing inward vesiculation. In this study, we have investigated the conformational dynamics of TRAF2-C through circular dichroism, fluorescence, and dynamic light scattering, performing temperature-dependent measurements. The data indicate that the protein retains its oligomeric state and most of its secondary structure, while displaying a significative increase in the heterogeneity of the tyrosines signal, increasing the temperature from ≈15 to ≈35 °C. The peculiar crowding of tyrosine residues (12 out of 18) at the three subunit interfaces and the strong dependence on the trimer concentration indicate that such conformational changes mainly involve the contact areas between each pair of monomers, affecting the oligomeric state. Molecular dynamic simulations in this temperature range suggest that the interfaces heterogeneity is an intrinsic property of the trimer that arises from the continuous, asymmetric approaching and distancing of its subunits. Such dynamics affect the results of molecular docking on the external protein surface using receptor peptides, indicating that the TRAF2-receptor interaction in the solution might not involve three subunits at the same time, as suggested by the static analysis obtainable from the crystal structure. These findings shed new light on the role that the TRAF2 oligomeric state might have in regulating the protein binding activity in vivo.

scholarly journals GENETIC INVOLVEMENT OF INTERLEUKIN 4 FOR ASTHMA AND IDENTIFICATION OF POTENTIAL PHYTOCHEMICAL SCAFFOLD THROUGH MOLECULAR DOCKING STUDIES

2018 ◽  
Vol 10 (1) ◽  
pp. 43 ◽  
Author(s):  
S. Sarithamol ◽  
Divya V. ◽  
Sunitha V. R. ◽  
Suchitra Surendran ◽  
V. L. Pushpa ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Small Molecules ◽  
In Silico ◽  
Mutational Analysis ◽  
Chromosome Region ◽  
Specific Treatment ◽  
Docking Studies ◽  
Interleukin 4 ◽  
Receptor Interaction ◽  
Drug Candidates

Objective: Interleukin 4, an important cytokine, has the major role in the immunomodulatory responses associated with asthma. The present study focused on the involvement of single nucleotide polymorphism variation (SNP) of interleukin 4 (IL4) in the development of disease, asthma and designing small molecules for the inhibition of IL4 through in silico strategy.Methods: Identification of disease causing SNP will be a wise approach towards the phenotype specific treatment. A human origin deleterious no synonymous SNP of IL4 were found out in the chromosome region 5q31-q33 (rs199929962) (T/C). Proteins of the corresponding nucleotide variation were identified and were subjected to characterization studies for selecting the most appropriate one for further mutational analysis and molecular docking studies.Results: Influence of microbes on SNP variation of IL4 gene leading to asthma was found to be insignificant by metagenomic studies. Gene responsive drugs were identified through environmental factor analysis. The drug candidates including corticosteroids were subjected to protein interaction studies by in silico means. The pharmacophoric feature derived from drug receptor interaction was utilized for virtual screening on a dataset of anti-inflammatory phytomolecules. The scaffolds of ellagic acid and quercetin were identified as potential nonsteroidal entities which can shield the asthmatic activities.Conclusion: Developing small molecules using these scaffolds taking interleukin 4 as a target will be an adequate solution for steroid resistant asthma.

Protein-Ligand Docking Methodologies and Its Application in Drug Discovery

2016 ◽  
pp. 196-219
Author(s):  
Sanchaita Rajkhowa ◽  
Ramesh C. Deka
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
Drug Design ◽  
High Throughput Screening ◽  
Docking Studies ◽  
Stable Complex ◽  
Scoring Functions ◽  
Binding Modes ◽  
Structure Based Drug Design ◽  
Modern Drug

Molecular docking is a key tool in structural biology and computer-assisted drug design. Molecular docking is a method which predicts the preferred orientation of a ligand when bound in an active site to form a stable complex. It is the most common method used as a structure-based drug design. Here, the authors intend to discuss the various types of docking methods and their development and applications in modern drug discovery. The important basic theories such as sampling algorithm and scoring functions have been discussed briefly. The performances of the different available docking software have also been discussed. This chapter also includes some application examples of docking studies in modern drug discovery such as targeted drug delivery using carbon nanotubes, docking of nucleic acids to find the binding modes and a comparative study between high-throughput screening and structure-based virtual screening.

P144 IN SILICO IDENTIFICATION OF PUTATITVE CLAUDIN CHANNEL BLOCKERS

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S30-S30
Author(s):  
Emma Wu ◽  
Priyanka Samanta ◽  
Ye Li ◽  
Le Shen ◽  
Fatemeh Khalili ◽  
...  
Keyword(s):  
In Silico ◽  
Homology Model ◽  
Docking Studies ◽  
Channel Blockers ◽  
Barrier Dysfunction ◽  
Dynamic Simulations ◽  
Epithelial Barrier Function ◽  
In Vitro Measurements ◽  
Potential Ligand

Abstract Compromised epithelial barrier function is known to be associated with inflammatory bowel disease (IBD) and may contribute to disease development. One mechanism of barrier dysfunction is increased expression of paracellular tight junction ion and water channels formed by claudins. Claudin-2 and -15 are two such channels. We hypothesize that blocking these channels could be a viable therapeutic approach to treat diarrhea in IBD. In an effort to develop blockers of these channels, we turn to our previously developed and validated in silico models of claudin-15 (Samanta et al. 2018). We reasoned that molecules that can bind with the interior of claudin pores can limit paracellular water and ion flux. Thus, we used docking algorithms to search for putative drugs that bind in the claudin-15 pore. AutoDock Vina (Scripps Research Institute) was initially used to assess rigid docking using small molecule ligand databases. The ligands were analyzed based on binding affinity to the pore and visualized using VMD (University of Illinois at Urbana-Champaign) for their potential blockage of the channel. Overall, a total of eight candidate ligands from the databases were identified: three from the UICentre database of 10000 ligands, one chemically similar structure identified in another online database (Chemspider), and four which are modifications on the chemical structure generated using ChemDraw. The analysis revealed that the eight ligands were docked in two predominant positions. In the first position, the ligands with more rings docked in an almost linear fashion and interacted with both D55 and D64 pore residues. In the second position of binding, the ligands were more flexible and could hence fold to interact only with D55 residues, thus biding predominantly in the center of the pores. To further evaluate these ligands, we will now turn to 1) flexible claudin-15 docking studies, 2) molecular dynamic simulations and, 3) in vitro measurements using monolayers induced to express claudin -15 and claudin-15 mutants. We also developed a claudin-2 homology model on which we will perform docking studies and in vitro measurements, which we expect will result in similar candidate ligands for blocking claudin-2. Finally, other databases will be analyzed for potential ligand blockers of claudin-2 and -15.

scholarly journals Phloroglucinol as a Potential Candidate against Trypanosoma congolense Infection: Insights from In Vivo, In Vitro, Molecular Docking and Molecular Dynamic Simulation Analyses

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 469
Author(s):  
Nasirudeen Idowu Abdulrashid ◽  
Suleiman Aminu ◽  
Rahma Muhammad Adamu ◽  
Nasir Tajuddeen ◽  
Murtala Bindawa Isah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Docking Studies ◽  
Binding Energies ◽  
Sub Saharan Africa ◽  
Dynamics Simulation ◽  
Potential Candidate ◽  
Inhibitory Effects ◽  
Hydrogen Bond Interaction

Sub-Saharan Africa is profoundly challenged with African Animal Trypanosomiasis and the available trypanocides are faced with drawbacks, necessitating the search for novel agents. Herein, the chemotherapeutic potential of phloroglucinol on T. congolense infection and its inhibitory effects on the partially purified T. congolense sialidase and phospholipase A2 (PLA2) were investigated. Treatment with phloroglucinol for 14 days significantly (p < 0.05) suppressed T. congolense proliferation, increased animal survival and ameliorated anemia induced by the parasite. Using biochemical and histopathological analyses, phloroglucinol was found to prevent renal damages and splenomegaly, besides its protection against T. congolense-associated increase in free serum sialic acids in infected animals. Moreover, the compound inhibited bloodstream T. congolense sialidase via mixed inhibition pattern with inhibition binding constant (Ki) of 0.181 µM, but a very low uncompetitive inhibitory effects against PLA2 (Ki > 9000 µM) was recorded. Molecular docking studies revealed binding energies of −4.9 and −5.3 kcal/mol between phloroglucinol with modeled sialidase and PLA2 respectively, while a 50 ns molecular dynamics simulation using GROMACS revealed the sialidase-phloroglucinol complex to be more compact and stable with higher free binding energy (−67.84 ± 0.50 kJ/mol) than PLA2-phloroglucinol complex (−77.17 ± 0.52 kJ/mol), based on MM-PBSA analysis. The sialidase-phloroglucinol complex had a single hydrogen bond interaction with Ser453 while none was observed for the PLA2-phloroglucinol complex. In conclusion, phloroglucinol showed moderate trypanostatic activity with great potential in ameliorating some of the parasite-induced pathologies and its anti-anemic effects might be linked to inhibition of sialidase rather than PLA2.

scholarly journals Identification of Potential Mpro Inhibitors for the Treatment of COVID-19 by Targeted Covalent Inhibition

2021 ◽  
Vol 6 (2) ◽  
pp. 1-20
Author(s):  
Dushyant V. Patel ◽  
Divya M. Teli ◽  
Ashish M. Kanhed ◽  
Nirav R. Patel ◽  
Bhavik S. Shah ◽  
...  
Keyword(s):  
Interaction Analysis ◽  
Covalent Binding ◽  
Receptor Interaction ◽  
Potential Candidate ◽  
Structural Protein ◽  
Michael Adduct ◽  
Curcumin Derivatives ◽  
Novel Coronavirus ◽  
Catalytic Dyad ◽  
Virtual Screening Approach

A novel coronavirus is the causative agent identified for the current COVID-19 outbreak. Globally, more than 43 million people have been infected by this virus. The total number of deaths has surpassed 1.6 million across 210 countries due to the current pandemic. Till date, there is no specific therapeutic agent available for its treatment. Mpro, a non-structural protein cleaves viral polyproteins into other non-structural proteins. Inhibition of Mpro could prevent the virus replication projecting it as a potential candidate for anti-COVID-19 drug development. The authors report herein 10 top-ranked curcumin derivatives as non-peptide covalent-binding Mpro inhibitors using systematic virtual screening approach. Detailed ligand-receptor interaction analysis conferred that the α,β-unsaturated carbonyl moiety of curcumin functions as a warhead to yield a Michael adduct with Cys145 of the catalytic dyad of Mpro. Collectively, these results have offered new high affinity molecules for the development of potential drugs for the treatment of COVID-19.

scholarly journals Transcriptomic profile of leg muscle during early growth and development in Haiyang yellow chicken

2021 ◽  
Vol 64 (2) ◽  
pp. 405-416
Author(s):  
Xuemei Yin ◽  
Yulin Wu ◽  
Shanshan Zhang ◽  
Tao Zhang ◽  
Genxi Zhang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Growth And Development ◽  
Developmental Stages ◽  
Insulin Signalling ◽  
Muscle Growth ◽  
Pairwise Comparison ◽  
Early Growth ◽  
Receptor Interaction ◽  
Potential Candidate ◽  
Chicken Muscle

Abstract. Skeletal muscle growth and development from embryo to adult consists of a series of carefully regulated changes in gene expression. This study aimed to identify candidate genes involved in chicken growth and development and to investigate the potential regulatory mechanisms of early growth in Haiyang yellow chicken. RNA sequencing was used to compare the transcriptomes of chicken muscle tissues at four developmental stages. In total, 6150 differentially expressed genes (DEGs) (|fold change| ≥ 2; false discovery rate (FDR) ≤ 0.05) were detected by pairwise comparison in female chickens. Functional analysis showed that the DEGs were mainly involved in the processes of muscle growth and development and cell differentiation. Many of the DEGs, such as MSTN, MYOD1, MYF6, MYF5, and IGF1, were related to chicken growth and development. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the DEGs were significantly enriched in four pathways related to growth and development: extracellular matrix (ECM)–receptor interaction, focal adhesion, tight junction, and insulin signalling pathways. A total of 42 DEGs assigned to these pathways are potential candidate genes for inducing the differences in growth among the four development stages, such as MYH1A, EGF, MYLK2, MYLK4, and LAMB3. This study identified a range of genes and several pathways that may be involved in regulating early growth.

scholarly journals Anti Hepatitis C Viral Drugs Remdesivir and Uprifosbuvir Derivatives Are Better Inhibitors of SARS Cov2 RNA-Dependent RNA Polymerase Determined by Docking Studies. .

2020 ◽  
Author(s):  
Pavan Gudipati ◽  
Shyamasri Biswas ◽  
pankaj goyal
Keyword(s):  
Hepatitis C ◽  
Rna Polymerase ◽  
Development Process ◽  
Docking Studies ◽  
Virus Infections ◽  
Autodock Vina ◽  
Rna Dependent Rna Polymerase ◽  
Positive Sense ◽  
Future Drug ◽  
Starting Model

SARS Cov2 RNA-dependent RNA polymerase (RdRp) is an enzyme that catalyzes the synthesis and replication of viral RNA from an RNA template. Our starting model for this study was (SARS-Cov-2) cryo-EM structure published recently (pdb ID 6m71). We have used docking studies to find a better inhibitor for the enzyme that can be used in the treatment of SARS-CoV2 infections. Recently, several inhibitors like Sofosbuvir, Ribavirin, and Remdesivir has been reported as strong inhibitors of this enzyme. Our results show an analogue of Remdesivir such as CHEMBL3120791 and analogue of Uprifosbuvir SCHEMBL20762917, SCHEMBL20733228 as better inhibitors than previously reported inhibitors of RNAdependent RNA polymerase. Using Autodock Vina and Pyrx software for virtual screening of ligands, we found four higher efficiency compounds CHEMBL3120791, SCHEMBL20762917 SCHEMBL20733228, and Uprifosbuvir. The binding constant of these ligands were -9.5 (Kcal/mol), -8.3 (Kcal/mol), -8.3 (Kcal/mol), -8.6 (Kcal/mol), respectively when tested on SARS-COV-2 nsp12. Active site interactions with the potential drug molecule are with residues Lys47, Tyr129, Ser784, His133, Ser709 for CHEMBL3120791, SCHEMBL20762917 SCHEMBL20733228. These molecules can be used in the future drug development process in the treatment of SARS-Cov2 infection. The molecules reported here are already under clinical trial for the treatment of HCV (Hepatitis C Virus) infections, which is similar to SARS Cov2, as both are positive-sense RNA Viruses.<br>

Sign in / Sign up

Export Citation Format

Share Document