2. Academic Validation
  3. A combined in silico and MD simulation approach to discover novel LpxC inhibitors targeting multiple drug resistant Pseudomonas aeruginosa

A combined in silico and MD simulation approach to discover novel LpxC inhibitors targeting multiple drug resistant Pseudomonas aeruginosa

  • Sci Rep. 2025 May 15;15(1):16900. doi: 10.1038/s41598-025-99215-1.
Awadh Alanazi # 1,  Sonia Younas # 2 3,  Muhammad Umer Khan 4,  Hammad Saleem 5,  Muharib Alruwaili 6,  Abualgasim Elgaili Abdalla 6,  Bi Bi Zainab Mazhari 7,  Khalid Abosalif 6,  Hasan Ejaz 6
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia. aaanazi@ju.edu.sa.
  • 2 Centre for Immunology and Infection (C2i), Hong Kong Science and Technology Park, Hong Kong SAR, China.
  • 3 School of Public Health, LKS Faculty of Medicine, HKU-Pasteur Research Pole, The University of Hong Kong, Hong Kong SAR, China.
  • 4 Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan.
  • 5 Institute of Pharmaceutical Sciences (IPS), University of Veterinary & Animal Sciences (UVAS), Lahore, Pakistan. hammad.saleem@uvas.edu.pk.
  • 6 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia.
  • 7 Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Qurayyat, Saudi Arabia.
  • # Contributed equally.
PMID: 40374903 DOI: 10.1038/s41598-025-99215-1
Abstract

Pseudomonas aeruginosa (P. aeruginosa), a member of the ESKAPE family, is the major cause of infections leading to increased morbidity and mortality due to multidrug resistance (MDR). One of the main proteins involved in the Raetz pathway is LpxC, which plays a significant role in anti-microbial resistance (AMR). Our study aimed to identify a novel compound to combat MDR due to the LpxC protein. It involved in silico methods comprising molecular docking, simulations, ADMET profiling, and DFT calculations. First, an ADMET and bioactivity evaluation of the 25 top-hit compounds retrieved from ligand-based virtual screening was performed, followed by molecular docking. The results revealed compound P-2 as the lead compound, which was further subjected to DFT analysis and molecular dynamics (MD) simulations. With these analyses, our in silico study identified P-2, 3-[(dimethylamino)methyl]-N-[(2 S)-1-(hydroxyamino)-1-oxobutan-2-yl]benzamide as a potential lead compound that may behave as a very potent inhibitor of LpxC for the development of targeted therapies against MDR P. aeruginosa.

Keywords

ADMET; Bioactivity; DFT; In silico; LpxC; MD simulation; MDR; Molecular docking; Toxicity.

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