Molecular modelling studies on ɑ7 nicotinic receptor allosteric modulators yields novel filter-based virtual...

Area of Science:

• Neuroscience
• Pharmacology
• Computational Chemistry

Background:

• The alpha-7 nicotinic acetylcholine receptor (α7 nAChR) is implicated in neurological disorders.
• Allosteric modulators, including positive (PAMs) and negative (NAMs), target α7 nAChRs, with PAMs holding greater therapeutic potential.
• Differentiating PAMs from NAMs based on structural and binding characteristics is crucial for drug discovery.

Purpose of the Study:

• To develop and validate a pharmacophore-based filtering strategy to discriminate between PAMs and NAMs targeting the α7 nAChR.
• To identify key structural and physicochemical properties that differentiate PAMs from NAMs.
• To enhance the efficiency of virtual screening for novel α7 nAChR PAMs.

Main Methods:

• Investigated physicochemical properties of known PAMs and NAMs using two databases.
• Developed distinct pharmacophores for PAMs and NAMs based on their properties.
• Utilized molecular docking to identify key amino acids in the α7 nAChR allosteric site for differential binding.
• Applied pharmacophore-based filtering in virtual screening and seeding experiments.

Main Results:

• PAMs were found to be larger and more polar than NAMs.
• Developed PAM pharmacophore successfully identified 94% of PAMs and excluded 71% of NAMs.
• Developed NAM pharmacophore successfully identified 82% of NAMs and excluded 85% of PAMs.
• Pharmacophore filtering increased the retrieval of true PAMs by up to five-fold in virtual screening.

Conclusions:

• The developed pharmacophore-based filtering technique is an effective tool for distinguishing α7 nAChR PAMs from NAMs.
• This method significantly improves the efficiency of identifying potent PAM molecules for therapeutic applications.
• The findings provide a valuable strategy for the discovery of novel modulators of α7 nicotinic receptors.