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

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.

AnchorDock for Blind Flexible Docking of Peptides to Proteins.

Due to increasing interest in peptides as signaling modulators and drug candidates, several methods for peptide docking to their target proteins are under active development. The "blind" docking problem, where the peptide-binding site on the protein surface is unknown, presents one of the current challenges in the field. AnchorDock protocol was developed by Ben-Shimon and Niv to address this challenge.This protocol narrows the docking search to the most relevant parts of the conformational space. This is achieved by pre-folding the free peptide and by computationally detecting anchoring spots on the surface of the unbound protein. Multiple flexible simulated annealing molecular dynamics (SAMD) simulations are subsequently carried out, starting from pre-folded peptide conformations, constrained to the various precomputed anchoring spots.Here, AnchorDock is demonstrated using two known protein-peptide complexes. A PDZ-peptide complex provides a relatively easy case due to the relatively small size of the protein, and a typical peptide conformation and binding region; a more challenging example is a complex between USP7N-term and a p53-derived peptide, where the protein is larger, and the peptide conformation and a binding site are generally assumed to be unknown. AnchorDock returned native-like solutions ranked first and third for the PDZ and USP7 complexes, respectively. We describe the procedure step by step and discuss possible modifications where applicable.