Simulated annealing molecular dynamics and ligand-receptor contacts analysis for pharmacophore modeling

Ligand-based pharmacophore modeling requires long list of inhibitors, while pharmacophores based on single ligand-receptor crystallographic structure can be too restricted or promiscuous.

This prompted us to combine simulated annealing molecular dynamics (SAMD) with ligand-receptor contacts analysis as means to construct pharmacophore model(s) from single ligand-receptor complex. Ligand-receptor contacts that survive numerous heating-cooling SAMD cycles are considered critical and are used to guide pharmacophore development.

This methodology was implemented to develop pharmacophores for acetylcholinesterase and protein kinase C-θ. The resulting models were validated by receiver-operating characteristic analysis and in vitro bioassay. Assay identified four new protein kinase C-θ inhibitors among captured hits, two of which exhibited nanomolar potencies.

The results illustrate the ability of the new method to extract valid pharmacophores from single ligand-protein complex.