In silico approaches to evaluate the molecular properties of organophosphate compounds to inhibit acetylcholinesterase activity in housefly

Parthiban Marimuthu, Yong-Jin Lee*, ByungHoon Kim, Seong S Seo

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

9 Citations (Scopus)


Organophosphate compounds (OPC) have become the primary choice as insecticides and are widely used across the world. Additionally, OPCs were also commonly used as a chemical warfare agent that triggers a great challenge to public safety. Exposure of OPCs to human causes immediate excitation of cholinergic neurotransmission through transient elevation of synaptic acetylcholine (ACh) levels and accumulations. Likewise, prolonged exposure of OPCs can affect the processes in immune response, carbohydrate metabolism, cardiovascular toxicity, and several others. Studies revealed that the toxicity of OPCs was provoked by inhibition of acetylcholinesterase (AChE). Therefore, combined in silico approaches - pharmacophore-based 3D-QSAR model; docking and Molecular Dynamics (MD) - were used to assess the precise and comprehensive effects of series of known OP-derived compounds together with its -log LD50 values. The selected five-featured pharmacophore model - AAHHR.61 - displayed the highest correlation (R2 = .9166), cross-validated coefficient (Q2 = .8221), F = 63.2, Pearson-R = .9615 with low RMSE = .2621 values obtained using five component PLS factors. Subsequently, the well-validated model was then used as a 3D query to search novel OPCs using a high-throughput virtual screening technique. Simultaneously, the docking studies predicted the binding pose of the most active OPC in the MdAChE binding pocket. Additionally, the stability of docking was verified using MD simulation. The results revealed that OP22 and predicted lead compounds bound tightly to S315 of MdAChE through potential hydrogen bond interaction over time. Overall, this study might provide valuable insight into binding mode of OPCs and hit compounds to inhibit AChE in housefly.

Original languageEnglish
Pages (from-to)307-320
Number of pages14
JournalJournal of biomolecular structure & dynamics
Issue number2
Publication statusPublished - Feb 2019
Externally publishedYes
MoE publication typeA1 Journal article-refereed


  • Acetylcholinesterase/chemistry
  • Animals
  • Binding Sites
  • Cholinesterase Inhibitors/chemistry
  • Houseflies/enzymology
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Molecular Conformation
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Organophosphates/chemistry
  • Protein Binding
  • Quantitative Structure-Activity Relationship


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