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A drug repurposing endeavor to discover a multi-targeting ligand against RhlR and LasR proteins from opportunistic human pathogen Pseudomonas aeruginosa

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Abstract

Pseudomonas aeruginosa is an opportunistic human pathogen. It synthesizes the poison called Hydrogen Cyanide (HCN). The synthesis of HCN is mediated by the enzyme HCN synthase which is obtained from the hcnABC operon and the transcription of the hcnABC operon is mediated by three proteins LasR, RhlR, and ANR. In our previous works, we analyzed the activation process of RhlR and LasR proteins by their cognate auto-inducer ligands (N-butanoyl-l-homoserine lactone and N-(3-oxododecanoyl)-homoserine lactone respectively). In this work, we attempted to identify some multi-targeting ligands which would be able to destroy the structural integrity of both the RhlR and LasR proteins using steered MD simulations. We used the virtual screening of ligand libraries, and for that purpose, we used the NCI drug database. We selected the top 4 ligands from our virtual screening experiments. We then tried to check their relative binding affinities with the LasR and RhlR proteins in comparison to their native auto-inducer ligands. Through this work, we were able to identify 4 such ligands which were capable of binding to both the RhlR and LasR proteins in a better way than their native auto-inducer ligands. The efficacies of these ligands to actually perturb the structural integrity of RhlR and LasR proteins could be tested in wet lab. The work is the first work in the field of structure-based drug design to come up with possible multi-targeting drug-like structures against the RhlR and LasR proteins from Pseudomonas aeruginosa.

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Funding

This study is funded by the UGC-SAP-DRS II and DST-PURSE-II, ICMR (sanction BIC/12(02)/2014) and University of Kalyani.

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Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Kalyani, Nadia, Kalyani, 741235, West Bengal, India

    Nilkanta Chowdhury & Angshuman Bagchi

  2. Department of Biotechnology, Sidho-Kanho-Birsha University, Ranchi-Purulia Road Campus, Near Sainik School, Purulia, 723104, West Bengal, India

    Nilkanta Chowdhury

Authors
  1. Nilkanta Chowdhury
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  2. Angshuman Bagchi
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AB conceptualized the work. NC carried out the experiments. AB and NC wrote the manuscript. All the authors agreed to submit the work.

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Correspondence to Angshuman Bagchi.

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Chowdhury, N., Bagchi, A. A drug repurposing endeavor to discover a multi-targeting ligand against RhlR and LasR proteins from opportunistic human pathogen Pseudomonas aeruginosa. J Mol Model 28, 295 (2022). https://doi.org/10.1007/s00894-022-05301-w

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