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

Abstract

Aim: Ligand-based pharmacophore modeling requires long list of inhibitors, while pharmacophores based on single ligand–receptor crystallographic structure can be too restricted or promiscuous. Methodology: 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. Results: 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. Conclusion: The results illustrate the ability of the new method to extract valid pharmacophores from single ligand–protein complex.