scholarly journals An In Silico Study of a Novel rpoB Insertion in a Cluster of Clinical Strains of Mycobacterium tuberculosis Highly-Rifampicin Resistant

2017 ◽  
Author(s):  
Maria Lucia R. Rossetti ◽  
Pedro Almeida da Silva ◽  
Raquel Maschmann ◽  
Andrea von Groll ◽  
Leonardo S. Esteves ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Virtual Screening ◽  
Rna Polymerase ◽  
In Silico ◽  
Chemotherapeutic Agents ◽  
Single Amino Acid ◽  
Mutant Form ◽  
Clinical Strains ◽  
In Silico Studies ◽  
Biological Cost

Rifampicin is one of the most important chemotherapeutic agents used in the treatment of tuberculosis. M. tuberculosis clinical strains resistant to rifampicin harbor mainly mutation in an 81-base pair region of rpoB. These mutations mainly consist of single amino acid substitutions. However insertions also can be related with rifampicin resistance strains. Herein, we described an insertion of 12 nucleotides in clinical isolates of M. tuberculosis resistant to rifampicin, all obtained from inmates. To evaluate the importance this insertion in surviving and drug resistance, it were carried out fitness experimental assays as well as in silico studies of 3D structural models, molecular docking simulations and virtual screening. The medical records of the seven patients showed all were previously treated to tuberculosis. Growth curves shown that the insertion determines a biological cost when compared to wild type rpoB and katG; or the double mutated rpoB S531L and katG S315T. From docking and molecular dynamics simulations it can be inferred that the insertion does not affect the process of synthesis of RNA transcripts. On the other hand, in the mutant RNAP-RIF complex rifampicin confirmed a low affinity interaction for the mutant form. Interesting, virtual screening for potential inhibitors for wtRNAP and mRNAP using a library of 1446 compounds approved by the FDA showed that the best ligands were mainly compounds with antibiotic activity, although the targets involved in the pharmacological action are other than RNAP. In conclusion, seven strains of M. tuberculosis RIF resistant that present an insertion of four amino acids in RNA polymerase showed by growth curve assays, a biological cost. Further, bioinformatics tools had characterized the putative drug resistance dynamic as well as the maintenance of RNA polymerase activity.

Design, Synthesis and In-Vitro Biological Activity of Some New 1,3-Thiazolidine-4-One Derivatives as Chemotherapeutic Agents Using Virtual Screening Strategies

2020 ◽  
Vol 16 ◽  
Author(s):  
Pragya Nayak ◽  
Monica Kachroo
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virtual Screening ◽  
In Silico ◽  
Cancer Cell Line ◽  
Inhibitory Response ◽  
Chemotherapeutic Agents ◽  
Acceptor Site ◽  
Hydrogen Bond Acceptor ◽  
Screening Strategies

: A series of new heteroaryl thiazolidine-4-one derivatives were designed and subjected to in-silico prioritization using various virtual screening strategies. Two series of thiazolidinone derivatives were synthesized and screened for their in-vitro antitubercular, anticancer, antileishmanial and antibacterial (Staphylococcus aureus; Streptococcus pneumonia; Escherichia coli; Pseudomonas aeruginosa) activities. The compounds with electronegative substitutions exhibited positive antitubercular activity, the derivatives possessing a methyl substitution exhibited good inhibitory response against breast cancer cell line MCF-7 while the compounds possessing a hydrogen bond acceptor site like hydroxyl and methoxy substitution in their structures exhibited good in-vitro antileishmanial activity. Some compounds exhibited potent activity against gram positive bacteria Pseudomonas aeruginosa as compared to the standards. Altogether, the designed compounds exhibited good in-vitro anti-infective potential which was in good agreement with the in-silico predictions and they can be developed as important lead molecules for anti-infective and chemotherapeutic drug research.

scholarly journals IN-SILICO SCREENING AGAINST ANTIMALARIAL TARGET PLASMODIUM FALCIPARUM ENOYL-ACYL CARRIER PROTEIN REDUCTASE

2017 ◽  
Vol 10 (17) ◽  
pp. 127
Author(s):  
Berwi Fazri Pamudi ◽  
Azizahwati Azizahwati ◽  
Arry Yanuar
Keyword(s):  
Plasmodium Falciparum ◽  
Virtual Screening ◽  
In Silico ◽  
Acyl Carrier Protein ◽  
Parasitic Infection ◽  
Antimalarial Drugs ◽  
Chemotherapeutic Agents ◽  
Effective Vaccine ◽  
Carrier Protein ◽  
In Silico Screening

  Objective: Malaria is a parasitic infection that causes worldwide health problems. The absence of an effective vaccine and Plasmodium strains that are resistant to antimalarial drugs emphasize the importance of developing new chemotherapeutic agents. The use of computers for in-silico screening, or virtual screening, is currently being developed as a method for discovering antimalarial drugs. One of the enzymes that can support the development of the malaria parasite is the Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR). Inhibition of these enzymes leads to Type II lipid biosynthesis inhibition on the parasite.Methods: This research investigates the use of virtual screening to find PfENR inhibitor candidates. A molecular docking method using GOLD software and the medicinal plants in Indonesia database will be used. This target has been optimized by the removal of residues and the addition of charge. Ligand is expected to be an inhibitor of PfENR.Results: In-silico screening, or virtual screening, found that the top five compounds with the highest GOLD score at trial are kaempferol 3-rhamnosyl- (1-3)-rhamnosyl-(1-6)-glucoside; cyanidin 3,5-di-(6-malonylglucoside); 8-hydroxyapigenin 8-(2’’, 4’’-disulfato glucuronide); epigallocatechin 3,5,-di- O-gallat; quercetin 3,4’-dimethyl ether 7-alpha-L-arabinofuranosyl-(1-6)-glucoside. They had GOLD scores of 94.73, 95.90, 86.46, 85.39, and 84.40, respectively.Conclusions: There are two candidate inhibitor compounds from tea (Camellia sinensis), which have potential for development as an antimalarial drug, which are kaempferol 3-rhamnosyl-(1-3)-rhamnosyl-(1-6)-glucoside and epigallocatechin 3,5,-di-O-gallate, with a GOLD score of 94.73 and 85.39, respectively.

scholarly journals Analysis Docking Of Plasmodium Falciparum Enoyl Acyl Carrier Protein Reductase (Pfenr) With Organic Compunds From Virtual Screening Of Herbal Database

2020 ◽  
Vol 3 (1) ◽  
pp. 127
Author(s):  
Nya Daniaty Malau ◽  
St Fatimah Azzahra
Keyword(s):  
Plasmodium Falciparum ◽  
Virtual Screening ◽  
In Silico ◽  
Fatty Acid Biosynthesis ◽  
Acyl Carrier Protein ◽  
Chemotherapeutic Agents ◽  
Effective Vaccine ◽  
Carrier Protein ◽  
Autodock Vina ◽  
In Silico Screening

Malaria is one of problematic infectious diseases worldwide. The absence of an effective vaccine and the spread of drug resistant strains of Plasmodium clearly indicate the necessity for the deveploment of new chemotherapeutic agents. Recent method being developed is searching a new drug of antimalarial using in silico screening, or also known as virtual screening. One of enzyme target that important for growth of the malaria parasite is Plasmodium falciparum Enoyl Acyl Carrier Protein Reductase (PfENR). Inhibition of this enzyme cause the fatty acid biosynthesis type II will be terminated. In this research, in silico screening was performed using AUTODOCK VINA software to find inhibitor candidates of PfENR by using ligands from the database of Medicinal Plants in Indonesia. On the AUTODOCK VINA software moleculer docking experiments were performed between ligands and macromolecule target PfENR. This target that has been optimized with residue removal and charges addition. Ligand is expected to be the PfENR inhibitors.

scholarly journals In Silico Screening of Available Drugs Targeting Non-Small Cell Lung Cancer Targets: A Drug Repurposing Approach

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 59
Author(s):  
Muthu Kumar Thirunavukkarasu ◽  
Utid Suriya ◽  
Thanyada Rungrotmongkol ◽  
Ramanathan Karuppasamy
Keyword(s):  
Drug Resistance ◽  
Virtual Screening ◽  
High Throughput ◽  
In Silico ◽  
Limiting Factor ◽  
Energy Calculation ◽  
Lead Compounds ◽  
Study Results ◽  
Glide Docking ◽  
High Throughput Virtual Screening

The RAS–RAF–MEK–ERK pathway plays a key role in malevolent cell progression in many tumors. The high structural complexity in the upstream kinases limits the treatment progress. Thus, MEK inhibition is a promising strategy since it is easy to inhibit and is a gatekeeper for the many malignant effects of its downstream effector. Even though MEK inhibitors are under investigation in many cancers, drug resistance continues to be the principal limiting factor to achieving cures in patients with cancer. Hence, we accomplished a high-throughput virtual screening to overcome this bottleneck by the discovery of dual-targeting therapy in cancer treatment. Here, a total of 11,808 DrugBank molecules were assessed through high-throughput virtual screening for their activity against MEK. Further, the Glide docking, MLSF and prime-MM/GBSA methods were implemented to extract the potential lead compounds from the database. Two compounds, DB012661 and DB07642, were outperformed in all the screening analyses. Further, the study results reveal that the lead compounds also have a significant binding capability with the co-target PIM1. Finally, the SIE-based free energy calculation reveals that the binding of compounds was majorly affected by the van der Waals interactions with MEK receptor. Overall, the in silico binding efficacy of these lead compounds against both MEK and PIM1 could be of significant therapeutic interest to overcome drug resistance in the near future.

scholarly journals In vitro and In silico studies on inhibitory effects of curcumin on multi drug resistance associated protein (MRP1) in retinoblastoma cells

2012 ◽  
Vol 8 (1) ◽  
pp. 13-19 ◽  
Author(s):  
Seethalakshmi Sreenivasan ◽  
Sathyabaarathi Ravichandran ◽  
Umashankar Vetrivel ◽  
Subramanian Krishnakumar
Keyword(s):  
Drug Resistance ◽  
In Silico ◽  
Multi Drug Resistance ◽  
Inhibitory Effects ◽  
Retinoblastoma Cells ◽  
In Silico Studies

In Silico ADMET and Docking Studies of Thiazolidinedione-acetic-acid Hybrids as Antidiabetics with Cardioprotection

2020 ◽  
Vol 17 (12) ◽  
pp. 1475-1484
Author(s):  
Deepanwita Maji ◽  
Subir Samanta ◽  
Vaishali M. Patil
Keyword(s):  
Acetic Acid ◽  
Amino Acid ◽  
Side Effects ◽  
In Silico ◽  
Methyl Esters ◽  
Antioxidant Properties ◽  
Docking Studies ◽  
Single Amino Acid ◽  
In Silico Admet ◽  
In Silico Studies

Background: Type-2-diabetes mellitus is associated with many side effects affecting vital body organs, especially heart. Thiazolidinediones are potent antidiabetics. Studies have proven that amino-acids and peptides promote glucose transport, have antioxidant properties, and fewer side effects, thus we designed hybrids by combining amino-acid esters and peptide esters with 2, 4 thiazolidinedione acetic acid moiety which can act as antidiabetic agent with cardioprotection properties. Methodology: In vitro ADME, toxicity, and docking studies were performed using Qikprop3.1.OSIRIS, PROTOX (Prediction of Rodent Oral Toxicity), and FlexX 2.1.3, respectively. Results: All the designed molecules belong to three sub-series, i.e. 2, 4-dioxothiazolidine-5-acetic acid single amino acid hybrid methyl esters, 2, 4-dioxothiazolidine-5-acetic acid dipeptide hybrid methyl esters and 2, 4-dioxothiazolidine-5-acetic acid tripeptide hybrid methyl esters. All molecules were non-toxic. SSMA2, SSMA14, SSMA49, and SSDM50 showed good docking scores in 2PRG and 2UV4, respectively. Conclusion: The selected in silico studies helped to design hybrids with less toxicity, target specificity with dual activity as potential anti-diabetic and cardioprotective agents.

Potential Candidates against COVID-19 Targeting RNA-Dependent RNA Polymerase: A Comprehensive Review

2021 ◽  
Vol 22 ◽  
Author(s):  
Neetu Agrawal ◽  
Ahsas Goyal
Keyword(s):  
Rna Polymerase ◽  
In Silico ◽  
Host Cells ◽  
Rna Dependent Rna Polymerase ◽  
In Vivo Experiments ◽  
Contagious Nature ◽  
In Silico Studies ◽  
Viral Enzyme

: Due to the extremely contagious nature of SARS-COV-2, it presents a significant threat to humans worldwide. A plethora of studies are going on all over the world to discover the drug to fight SARS-COV-2. One of the most promising targets is RNA-dependent RNA polymerase (RdRp), responsible for viral RNA replication in host cells. Since RdRp is a viral enzyme with no host cell homologs, it allows the development of selective SARS-COV-2 RdRp inhibitors. A variety of studies used in silico approaches for virtual screening, molecular docking, and repurposing of already existing drugs and phytochemicals against SARS-COV-2 RdRp. This review focuses on collating compounds possessing the potential to inhibit SARS-COV-2 RdRp based on in silico studies to give medicinal chemists food for thought so that the existing drugs can be repurposed for the control and treatment of ongoing COVID-19 pandemic after performing in vitro and in vivo experiments.

scholarly journals Evaluation of Phytochemicals of Cassia occidentalis L. for their Binding Affinities to SARS-CoV-2 3C-Like Protease: An in Silico Approach

2020 ◽  
pp. 8-14
Author(s):  
Tohmina Afroze Bondhon ◽  
Md. Aynal Haque Rana ◽  
Anamul Hasan ◽  
Rownak Jahan ◽  
Khoshnur Jannat ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Virtual Screening ◽  
In Silico ◽  
Binding Affinities ◽  
Autodock Vina ◽  
Cassia Occidentalis ◽  
Main Protease ◽  
In Silico Studies ◽  
The World ◽  
Docking Approach

Aims: Corona virus SARS-CoV-2, otherwise known as COVID-19 has created a pandemic resulting in social and financial crisis throughout the world. The virus has no known drugs or vaccines for preventive or therapeutic purposes. The objective of the present study was to screen phytochemicals from Cassia occidentalis L. in virtual screening (in silico) studies to evaluate their potential of binding to the main 3C-like protease of the virus and so stop its replication. Study Design: Molecular docking approach was used for virtual screening studies. Place and Duration of Study: University of Development Alternative between April and July 2020. Methodology: Molecular docking (blind) were done with the help of Autodock Vina. We have used the pdb file (6LU7) of the main protease of SARS-CoV-2 3C-like protease or SARS-CoV-2 3CLpro (monomeric form) to study binding of the phytochemicals. Results: Of the nine phytochemicals studied, the C-glycosidic flavonoids, cassiaoccidentalins A-C demonstrated excellent binding affinities to the protease. The compounds bound to the active site of the protease with binding energy values of -8.2 to-8.4 kcal/mol. Conclusion: The in silico studies suggest that the compounds merit actual COVID-19 inhibitory tests and have potential for anti-COVID-19 use.

scholarly journals Computational Saturation Mutagenesis to predict structural consequences of systematic mutations on protein stability and rifampin interactions in the β subunit of RNA polymerase inMycobacterium leprae

2019 ◽  
Author(s):  
Sundeep Chaitanya Vedithi ◽  
Carlos H. M. Rodrigues ◽  
Stephanie Portelli ◽  
Marcin J. Skwark ◽  
Madhusmita Das ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Rna Polymerase ◽  
In Silico ◽  
Growth Patterns ◽  
Diagnostic Methods ◽  
Saturation Mutagenesis ◽  
Mode Analysis ◽  
Relative Solvent Accessibility ◽  
Β Subunit ◽  
Rifampin Resistance

ABSTRACTIn contrast to the situation with tuberculosis, rifampin resistance in leprosy may remain undetected due to the lack of rapid and effective diagnostic methods. A quick and reliable method is essential to determine the impacts of emerging detrimental mutations. The functional consequences of missense mutations within the β-subunit of RNA polymerase inMycobacterium leprae(M. leprae) contribute to phenotypic rifampin resistance outcomes in leprosy. Here we reportin-silicosaturation mutagenesis of all residues in the β-subunit of RNA polymerase to all other 19 amino acid types and predict their impacts on overall thermodynamic stability, on interactions at subunit interfaces, and on β-subunit-RNA and rifampin affinities using state-of-the-art structure, sequence and normal mode analysis-based methods. A total of 21,394 mutations were analysed, and it was noted that mutations in the conserved residues that line the active-site cleft show largely destabilizing effects, resulting in increased relative solvent accessibility and concomitant decrease in depth of the mutant residues. The mutations at residues S437, G459, H451, P489, K884 and H1035 are identified as extremely detrimental as they induce highly destabilizing effects on the overall stability, nucleic acid and rifampin affinities. Destabilizing effects were predicted for all the experimentally identified rifampin-resistant mutations inM. lepraeindicating that this model can be used as a surveillance tool to monitor emerging detrimental mutations conferring rifampin resistance in leprosy.AUTHOR SUMMARYEmergence of primary and secondary drug resistance to rifampin in leprosy is a growing concern and poses threat to the leprosy control and elimination measures globally. In the absence of an effectivein-vitrosystem to detect and monitor phenotypic rifampin resistance in leprosy, most of the diagnosis relies on detecting mutations in the drug resistance determining regions of therpoBgene that encodes the β subunit of RNA polymerase inM. leprae. Few labs in the world perform mouse food pad propagation ofM. lepraein the presence of drugs (rifampin) to determine growth patterns and confirm resistance, however the duration of these methods lasts from 8 to 12 months making them impractical for diagnosis. Understanding molecular mechanisms of drug resistance is vital to associating mutations to clinical resistance outcomes in leprosy. Here we propose anin-silicosaturation mutagenesis approach to comprehensively elucidate the structural implications of any mutations that exist or can arise in the β subunit of RNA polymerase inM. leprae. Most of the predicted mutations may not occur inM. lepraedue to fitness costs but the information thus generated by this approach help decipher the impacts of mutations across the structure and conversely enable identification of stable regions in the protein that are least impacted by mutations (mutation coolspots) which can be a choice for small molecule binding and structure guided drug discovery.

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