Scholarlink

Purpose <p><i>Enterococcus faecium</i> is a nosocomial infective pathogen exhibiting extraordinary levels of Antimicrobial Resistance (AMR), effectively rising as a menace threatening global public health. The widespread prevalence of Multidrug-Resistance (MDR) in the clinical strains of <i>E. faecium </i>has brought forth an urgent demand for new antimicrobial therapeutic agents. In this proposed study, a comprehensive computational workflow has been implemented to prioritize marine natural products (MNPs) as potential inhibitors for disrupting <i>E. faecium</i> activity.</p> Methodology <p>The selected drug target, D-Alanine-D-Alanyl Carrier Protein Ligase (DltA), encoded by the <i>DltA</i> gene is involved in various pathogenic functionalities of the organism, including biofilm formation, cellular viability and virulence. For the prepared protein target, a multi-tier virtual screening workflow encompassing molecular docking, MM/GBSA binding free energy calculations and pharmacokinetic profiling was performed, using the CMNPD and SWMD marine-derived compound libraries.</p> Results <p>Four promising MNPs (CMNPD29054, CMNPD20882, CMNPD28723, and SWMDRR053) were identified, exhibiting favourable docking scores (–9.31 to –9.81 kcal/mol) and MM/GBSA binding energies (–44.25 kcal/mol to –69.58 kcal/mol). The shortlisted MNPs displayed favourable ADME/T Properties, while the energy gap values ranging from 0.161 eV to 0.197 eV, deduced from the DFT analysis illustrates their chemical reactivity and promising electronic properties. Molecular dynamics simulation (MDS) performed for the protein-ligand complexes, confirm their structural stability, as evident from the consistent molecular trajectory profiles. Principal component analysis (PCA) and free energy landscape (FEL) assessments confirmed structural stability and overall rigidity of the MNP-DltA complexes.</p> Conclusion <p>Collectively, this study provides a computational foundation for further experimental validation and the findings suggest that the proposed MNPs could act as potent DltA inhibitors to combat drug resistance in <i>E. faecium</i>.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Multi-Tier Virtual Screening Driven Discovery of Marine Natural Products as Potential DltA Inhibitors in Drug-Resistant Enterococcus faecium

  • 期刊论文

  • 发表日期：

    2026年4月1日

查看全文
  • Pradeep Kumar Sriram,
  • Manikandan Jayaraman,
  • Prabhu Dhamodharan,
  • Maharaja Muthuvairam Subbulakshmi,
  • Jeyakanthan Jeyaraman

摘要

Purpose

Enterococcus faecium is a nosocomial infective pathogen exhibiting extraordinary levels of Antimicrobial Resistance (AMR), effectively rising as a menace threatening global public health. The widespread prevalence of Multidrug-Resistance (MDR) in the clinical strains of E. faecium has brought forth an urgent demand for new antimicrobial therapeutic agents. In this proposed study, a comprehensive computational workflow has been implemented to prioritize marine natural products (MNPs) as potential inhibitors for disrupting E. faecium activity.

Methodology

The selected drug target, D-Alanine-D-Alanyl Carrier Protein Ligase (DltA), encoded by the DltA gene is involved in various pathogenic functionalities of the organism, including biofilm formation, cellular viability and virulence. For the prepared protein target, a multi-tier virtual screening workflow encompassing molecular docking, MM/GBSA binding free energy calculations and pharmacokinetic profiling was performed, using the CMNPD and SWMD marine-derived compound libraries.

Results

Four promising MNPs (CMNPD29054, CMNPD20882, CMNPD28723, and SWMDRR053) were identified, exhibiting favourable docking scores (–9.31 to –9.81 kcal/mol) and MM/GBSA binding energies (–44.25 kcal/mol to –69.58 kcal/mol). The shortlisted MNPs displayed favourable ADME/T Properties, while the energy gap values ranging from 0.161 eV to 0.197 eV, deduced from the DFT analysis illustrates their chemical reactivity and promising electronic properties. Molecular dynamics simulation (MDS) performed for the protein-ligand complexes, confirm their structural stability, as evident from the consistent molecular trajectory profiles. Principal component analysis (PCA) and free energy landscape (FEL) assessments confirmed structural stability and overall rigidity of the MNP-DltA complexes.

Conclusion

Collectively, this study provides a computational foundation for further experimental validation and the findings suggest that the proposed MNPs could act as potent DltA inhibitors to combat drug resistance in E. faecium.

Graphical Abstract