A comprehensive computational mutation structurefunction approach for determining potential drug target sites in poliovirus 2A protease

Younus, Amna; Bhatti, Muhammad Faraz

doi:10.4314/tjpr.v16i12.6

Cited by 2 publications

(2 citation statements)

References 42 publications

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“…Computational analysis of the protein proved it to be a better and suitable drug target against polio. Results are very much in accordance with the author's previous work using mutational samples of 2A protease [45,46]. Use of computational approaches to identify more potential drug binding sites in the conserved regions will lead to better drug design methods in the years ahead.…”

Section: Preprintssupporting

confidence: 88%

Characterization of Recombinant Poliovirus 2A Protease; A Potential Anti-Viral Drug Target

Younus¹,

Bhatti²,

Virk³

et al. 2018

Preprint

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Poliovirus 2A protease (PV2Apro) plays a vital role in viral replication and down-regulation of host cell protein synthesis. In order to understand more concerning PV2Apro, the protein was over-expressed in bacteria following amplification using sense and antisense primers and cloning in pET15b. Several expression hosts were tested and BL21 (DE3) pLysS cells gave the best expression of PV2Apro with minimal unwanted protein expression following IPTG induction. The 2Apro protein was purified to homogeneity using column chromatography, its solubility determined and its molecular weight and composition determined by MALDI-TOF mass spectrometry. The protease was found in the insoluble fraction and the purified protein had a slightly lower molecular weight than predicted. Moreover, three dimensional structure was modelled using template 1z8r with 58% identity and validated using ramachandran plot. Results revealed that most of the residues lie in favoured and allowed regions. These findings could help in a better understanding of PV2Apro structure and inhibition thus, highlighting potential targets for antiviral drug development.

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Section: Preprintssupporting

confidence: 88%

Characterization of Recombinant Poliovirus 2A Protease; A Potential Anti-Viral Drug Target

Younus¹,

Bhatti²,

Virk³

et al. 2018

Preprint

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“…Sequencing results showed some mutations in the protease, which were then employed for structural and drug binding sites analysis using various in silico tools, including Swiss modeling [ 15 ], Volume Area Dihedral Angle Reporter (VADAR) [ 16 ], COACH/I-Tasser (Interative Threading ASSEmbly Refiniment) [ 17 ], subCELlular LOcalization predictor (CELLO) V 2.5 [ 18 ], and Tm Finder [ 19 , 20 ]. Important ligand interactions have been identified among conserved regions of the protein, amplified from the two blood samples of poliovirus type 1 [ 20 ]. This study aims to identify drug targets of poliovirus 2Aprotease (Type I, II and III) from all sequences retrieved from the National Center for Biotechnology Information (NCBI).…”

Section: Introductionmentioning

confidence: 99%

Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches

Younus

Munawar

Bhatti

et al. 2018

Genes

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Polio viral proteinase 2A performs several essential functions in genome replication. Its inhibition prevents viral replication, thus making it an excellent substrate for drug development. In this study, the three-dimensional structure of 2A protease was determined and optimized by homology modelling. To predict the molecular basis of the interaction of small molecular agonists, docking simulations were performed on a structurally diverse dataset of poliovirus 2A protease (PV2Apr°) inhibitors. Docking results were employed to identify high risk missense mutations that are highly damaging to the structure, as well as the function, of the protease. Intrinsic disorder regions (IDRs), drug binding sites (DBS), and protein stability changes upon mutations were also identified among them. Our results demonstrated dominant roles for Lys 15, His 20, Cys 55, Cys 57, Cys 64, Asp 108, Cys 109 and Gly 110, indicating the presence of various important drug binding sites of the protein. Upon subjecting these sites to single-nucleotide polymorphism (SNP) analysis, we observed that out of 155 high risk SNPs, 139 residues decrease the protein stability. We conclude that these missense mutations can affect the functionality of the 2A protease, and that identified protein binding sites can be directed for the attachment and inhibition of the target proteins.

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A comprehensive computational mutation structurefunction approach for determining potential drug target sites in poliovirus 2A protease

Cited by 2 publications

References 42 publications

Characterization of Recombinant Poliovirus 2A Protease; A Potential Anti-Viral Drug Target

Characterization of Recombinant Poliovirus 2A Protease; A Potential Anti-Viral Drug Target

Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches

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