Dataset Information

Haplosaurus computes protein haplotypes for use in precision drug design.

ABSTRACT: Selecting the most appropriate protein sequences is critical for precision drug design. Here we describe Haplosaurus, a bioinformatic tool for computation of protein haplotypes. Haplosaurus computes protein haplotypes from pre-existing chromosomally-phased genomic variation data. Integration into the Ensembl resource provides rapid and detailed protein haplotypes retrieval. Using Haplosaurus, we build a database of unique protein haplotypes from the 1000 Genomes dataset reflecting real-world protein sequence variability and their prevalence. For one in seven genes, their most common protein haplotype differs from the reference sequence and a similar number differs on their most common haplotype between human populations. Three case studies show how knowledge of the range of commonly encountered protein forms predicted in populations leads to insights into therapeutic efficacy. Haplosaurus and its associated database is expected to find broad applications in many disciplines using protein sequences and particularly impactful for therapeutics design.

SUBMITTER: Spooner W

PROVIDER: S-EPMC6175845 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Haplosaurus computes protein haplotypes for use in precision drug design.

Spooner William W McLaren William W Slidel Timothy T Finch Donna K DK Butler Robin R Campbell Jamie J Eghobamien Laura L Rider David D Kiefer Christine Mione CM Robinson Matthew J MJ Hardman Colin C Cunningham Fiona F Vaughan Tristan T Flicek Paul P Huntington Catherine Chaillan CC

Nature communications 20181008 1

Selecting the most appropriate protein sequences is critical for precision drug design. Here we describe Haplosaurus, a bioinformatic tool for computation of protein haplotypes. Haplosaurus computes protein haplotypes from pre-existing chromosomally-phased genomic variation data. Integration into the Ensembl resource provides rapid and detailed protein haplotypes retrieval. Using Haplosaurus, we build a database of unique protein haplotypes from the 1000 Genomes dataset reflecting real-world pro ...[more]

PMID: 30297836

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Project description:Bacterial brown stripe disease caused by Acidovorax oryzae is a major threat to crop yields, and the current reliance on pesticides for control is unsustainable due to environmental pollution and resistance. To address this, bacterial-based ligands have been explored as a potential treatment solution. In this study, we developed a protein-protein interaction (PPI) network for A. oryzae by utilizing shared differentially expressed genes (DEGs) and the STRING database. Using a maximal clique centrality (MCC) approach through CytoHubba and Network Analyzer, we identified hub genes within the PPI network. We then analyzed the genomic data of the top 10 proteins, and further narrowed them down to 2 proteins by utilizing betweenness, closeness, degree, and eigenvector studies. Finally, we used molecular docking to screen 100 compounds against the final two proteins (guaA and metG), and Enfumafungin was selected as a potential treatment for bacterial resistance caused by A. oryzae based on their binding affinity and interaction energy. Our approach demonstrates the potential of utilizing bioinformatics and molecular docking to identify novel drug candidates for precision treatment of bacterial brown stripe disease caused by A. oryzae, paving the way for more targeted and sustainable control strategies. The efficacy of Enfumafungin in inhibiting the growth of A. oryzae strain RS-1 was investigated through both computational and wet lab methods. The models of the protein were built using the Swiss model, and their accuracy was confirmed via a Ramachandran plot. Additionally, Enfumafungin demonstrated potent inhibitory action against the bacterial strain, with an MIC of 100 µg/mL, reducing OD600 values by up to 91%. The effectiveness of Enfumafungin was further evidenced through agar well diffusion assays, which exhibited the highest zone of inhibition at 1.42 cm when the concentration of Enfumafungin was at 100 µg/mL. Moreover, Enfumafungin was also able to effectively reduce the biofilm of A. oryzae RS-1 in a concentration-dependent manner. The swarming motility of A. oryzae RS-1 was also found to be significantly inhibited by Enfumafungin. Further validation through TEM observation revealed that bacterial cells exposed to Enfumafungin displayed mostly red fluorescence, indicating destruction of the bacterial cell membrane.

Dataset Information

Haplosaurus computes protein haplotypes for use in precision drug design.

Publications

Haplosaurus computes protein haplotypes for use in precision drug design.

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