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<p>Tuberculosis remains a global health challenge, necessitating the discovery of novel inhibitors against <i>Mycobacterium tuberculosis</i>. This study investigates the potential inhibitory activity of phytochemicals from <i>Azadirachta indica</i> (Neem) against Decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1), a validated target involved in cell wall biosynthesis. The DprE1 structure (PDB: 4FDP) and a total of 25 selected ligands of A. indica were retrieved and prepared using the Schrodinger Maestro suite. Functional enrichment and network analysis were conducted using STRING and Cytoscape. Molecular docking (Glide XP) was performed, followed by 100 ns molecular dynamics (MD) simulations using Desmond to evaluate the stability of the protein–ligand complexes. Pharmacokinetic and toxicity profiles were predicted using the pkCSM server. Network analysis supported the role of DprE1 as a key node in mycobacterial cell wall organization. Molecular docking identified Quercetin as the top-ranked candidate with a binding affinity of − 7.9 kcal/mol, comparable to the reference inhibitor BTZ043. MD simulations indicated that the DprE1-Quercetin complex maintained stable interactions, with a calculated binding free energy (ΔG_bind) of − 51.52 kcal/mol compared to − 39.75 kcal/mol for BTZ043. Quercetin formed consistent hydrogen bond interactions with ASP318 and TYR314. ADMET predictions suggested that while BTZ043 exhibited higher intestinal absorption, Quercetin demonstrated a more favorable predicted safe compound, including the absence of AMES toxicity. Findings suggest that quercetin may serve as a promising inhibitor candidate, compared to the control inhibitor BTZ043, but requires further studies to better ascertain its efficacy as an anti-tubercular agent.</p>

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In-silico evaluation of Azadirachta indica (neem) against DprE1 of Mycobacterium tuberculosis with functional characterisation

  • 期刊论文

  • 发表日期：

    2026年6月20日

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  • Tolulope Sharon Rumide,
  • Abidemi Esther Ojo,
  • Regina Oghenevwede Golagha,
  • Aanuoluwapo Alake,
  • Zainab Ajoke Suleiman,
  • Lilian Oluchi Nwagbara,
  • Oluwagbemisola Victoria Alu,
  • Aisha Eniola Olayiwola,
  • Mustapha Alkasim,
  • Adebola Sunmola,
  • Mayowa Agbi,
  • Abubakar Lawal Shehu,
  • Bright Okoroma,
  • Muhammad Mubarak Dabo,
  • Oluwatobi Mary Ajayi,
  • Muhammed Robiu Asinmi

摘要

Tuberculosis remains a global health challenge, necessitating the discovery of novel inhibitors against Mycobacterium tuberculosis. This study investigates the potential inhibitory activity of phytochemicals from Azadirachta indica (Neem) against Decaprenylphosphoryl-β-D-ribose 2′-epimerase (DprE1), a validated target involved in cell wall biosynthesis. The DprE1 structure (PDB: 4FDP) and a total of 25 selected ligands of A. indica were retrieved and prepared using the Schrodinger Maestro suite. Functional enrichment and network analysis were conducted using STRING and Cytoscape. Molecular docking (Glide XP) was performed, followed by 100 ns molecular dynamics (MD) simulations using Desmond to evaluate the stability of the protein–ligand complexes. Pharmacokinetic and toxicity profiles were predicted using the pkCSM server. Network analysis supported the role of DprE1 as a key node in mycobacterial cell wall organization. Molecular docking identified Quercetin as the top-ranked candidate with a binding affinity of − 7.9 kcal/mol, comparable to the reference inhibitor BTZ043. MD simulations indicated that the DprE1-Quercetin complex maintained stable interactions, with a calculated binding free energy (ΔG_bind) of − 51.52 kcal/mol compared to − 39.75 kcal/mol for BTZ043. Quercetin formed consistent hydrogen bond interactions with ASP318 and TYR314. ADMET predictions suggested that while BTZ043 exhibited higher intestinal absorption, Quercetin demonstrated a more favorable predicted safe compound, including the absence of AMES toxicity. Findings suggest that quercetin may serve as a promising inhibitor candidate, compared to the control inhibitor BTZ043, but requires further studies to better ascertain its efficacy as an anti-tubercular agent.