Employing virtual screening and molecular dynamics simulations for identifying hits against the active cholera toxin

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Cholera poses a significant global health challenge, causing millions of infections annually.
• The cholera toxin's ADP ribosyltransferase activity leads to severe water and electrolyte loss.
• The active cholera toxin, a heterodimer of a Vibrio cholerae subunit and human ADP Ribosylation Factor (ARF), is a promising but under-explored drug target.

Purpose of the Study:

• To identify small molecule inhibitors targeting the protein-protein interface (PPI) of the active cholera toxin.
• To explore the druggability of the A1-ARF interface for novel cholera therapeutics.
• To screen an alkaloid library for compounds that can disrupt cholera toxin function.

Main Methods:

• Utilized a sequential docking and scoring strategy combined with molecular dynamics (MD) simulations.
• Employed docking algorithms (Glide SP, Glide XP) and AutoDock for virtual screening of 9,175 ADMET-screened alkaloids.
• Validated the stability of hit-toxin complexes using MD simulations and analyzed hydrogen bond occupancies.

Main Results:

• Identified three potential alkaloid inhibitors against the active cholera toxin's PPI.
• Two compounds, A6225 (7-formyldehydrothalicsimidine) and A16503 (1,2,7,8-tetrahydroxy dibenz[cd,f]indol-4(5H)-one), formed stable complexes with the toxin.
• MD simulations confirmed stable hydrogen bonds between the identified alkaloids and the toxin's PPI.

Conclusions:

• A6225 and A16503 are promising lead compounds for developing new anti-cholera drugs.
• The study validates the A1-ARF interface as a druggable target for cholera intervention.
• These identified alkaloids can serve as valuable reference compounds for future drug discovery efforts against cholera.