Investigation of vital pathogenic target orotate phosphoribosyltransferases (OPRTase) from Thermus thermophilus HB8: Phylogenetic and molecular modeling approach

Kanagarajan, Surekha; Prabhu, Dhamodharan; Mariadasse, Richard; Nachiappan, Mutharasappan; Biswal, Jayashree; Jeyakanthan, Jeyaraman

doi:10.1016/j.gene.2016.02.006

Cited by 22 publications

(7 citation statements)

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“…The top 5 inhibitors with the highest docking scores and minimum binding energies were analysed for their pharmacokinetic properties such ADME (Absorption, Distribution, Metabolism, Elimination or Toxicity) and drug likeliness [ 90 , 91 ]. The QikProp module of the “Schrodinger Suite 2019” was utilized to evaluate the drug likeliness by employing the Lipinski’s rule of five [ 39 ] and various pharmacokinetic properties such as probable Hydrogen bonding atoms; Human Oral Absorption (<25%: poor; >above 80%: good); QP LogS (Predicted aqueous solubility of the compounds, acceptable range is -6.0 to -0.5) and the IC 50 values for blockage of the human Ether-a-go-go-Related Gene (hERG) K + channels (< -5: satisfactory)[ 92 ].…”

Section: Methodsmentioning

confidence: 99%

Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

et al. 2021

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Apart from the canonical fingers, palm and thumb domains, the RNA dependent RNA polymerases (RdRp) from the viral order Nidovirales possess two additional domains. Of these, the function of the Nidovirus RdRp associated nucleotidyl transferase domain (NiRAN) remains unanswered. The elucidation of the 3D structure of RdRp from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), provided the first ever insights into the domain organisation and possible functional characteristics of the NiRAN domain. Using in silico tools, we predict that the NiRAN domain assumes a kinase or phosphotransferase like fold and binds nucleoside triphosphates at its proposed active site. Additionally, using molecular docking we have predicted the binding of three widely used kinase inhibitors and five well characterized anti-microbial compounds at the NiRAN domain active site along with their drug-likeliness. For the first time ever, using basic biochemical tools, this study shows the presence of a kinase like activity exhibited by the SARS-CoV-2 RdRp. Interestingly, a well-known kinase inhibitor- Sorafenib showed a significant inhibition and dampened viral load in SARS-CoV-2 infected cells. In line with the current global COVID-19 pandemic urgency and the emergence of newer strains with significantly higher infectivity, this study provides a new anti-SARS-CoV-2 drug target and potential lead compounds for drug repurposing against SARS-CoV-2.

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Section: Methodsmentioning

confidence: 99%

Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

et al. 2021

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“…One sequence from each clade was taken and their 3-D structure was superimposed to understand based on the secondary structure element. The structure based phylogenetic tree was constructed and the relation between the protein structures was analyzed [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

“…The retrieved 33 OBPs sequences were used to develop the 3-D model of protein using Swiss Model [ 18 ] and 10 structures taken from PDB database were considered as receptor molecules. The OBPs proteins were prepared and refined using protein preparation wizard implemented in the Schrodinger software suite [ 22 ]. The hydrogen atoms were consistently added to the protein structures with the pH 7.0±2.0 subsequently minimized with Optimized Potential for Liquid Simulation (OPLS-2005) all atom force field [ 23 ].…”

Section: Methodsmentioning

confidence: 99%

Insights from the Molecular modeling, docking analysis of illicit drugs and Bomb Compounds with Honey Bee Odorant Binding Proteins (OBPs)

et al. 2018

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Analysis of honeybee PBPs is of interest in the development of Biosensor applications. We described the predicted binding of 19 such compounds with 43-honey bee OBPs using molecular modeling, docking and phylogenetic analysis. Therefore, training the honeybees using preferred compounds formulate the bees to identify the illicit drugs and bomb compounds. Consequently, high docking score produced complex such OBP16-N-Phenyl-2-Napthalamine (-12.25k/mol), 3BJH-Crack Cocaine (-11.75k/mol), OBP10-Methadone (- 11.71k/mol), 1TUJ-Dronobinal Cannabis (-11.66k/mol), OBP13-Plasticizer (-11.27k/mol) and OBP24-Ecstasy (-10.89 k/mol) can be used to identify the compounds using biosensor application. The chemical reaction of the compounds for olfactory sensory was analyzed using DFT (Density Functional Theory) studies. Some of these compounds show high binding OBPs across distant phylogeny.

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“…At first the medical literature was retrospectively reviewed and well known M. tuberculosis protein target was chosen (Table 1) then they were downloaded in pdb format from protein Data Bank [20]. They were docked via Arguslab software version 4.0.1.…”

Section: Methodsmentioning

confidence: 99%

Similarity in the Amino Acid Sequences of Mycobacterium tuberculosis Protein Targets Involved in Binding Sites of Docking with Thiacetazone

Mafakheri¹,

Sardari²

2016

Pharm Anal Acta

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Although according to WHO document, between 1990 and 2015, both TB mortality and its incidence has been fallen over 47% worldwide, the spread of multidrug-resistant strains of Mycobacterium tuberculosis reveals clearly that the efforts to find new drugs should not be stopped and the pathogenic microorganisms develop resistance. More extended knowledge about existing drugs is critical to design new and more effective medicines. In this study, we report the amino acid sequences involved in binding sites of 70 M. tuberculosis protein targets' docked with Thiacetazone (TAC), one of the extensively used antitubercular drug that is used in combination with other antitubercular agents to break multi-drug resistant TB. Categorization of protein targets was performed on the basis of the free energy of binding for the docked compounds. Comparison of the binding sites with the aim of ClustalW application indicated huge similarities in their amino acid sequences among target complexes.

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Investigation of vital pathogenic target orotate phosphoribosyltransferases (OPRTase) from Thermus thermophilus HB8: Phylogenetic and molecular modeling approach

Cited by 22 publications

References 50 publications

Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

Characterization of the NiRAN domain from RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV-2

Insights from the Molecular modeling, docking analysis of illicit drugs and Bomb Compounds with Honey Bee Odorant Binding Proteins (OBPs)

Similarity in the Amino Acid Sequences of Mycobacterium tuberculosis Protein Targets Involved in Binding Sites of Docking with Thiacetazone

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