Pharmacophore Models Derived From Molecular Dynamics Simulations of Protein-Ligand Complexes: A Case Study

A single, merged pharmacophore hypothesis is derived combining 2000 pharmacophore models obtained during a 20 ns molecular dynamics simulation of a protein-ligand complex with one pharmacophore model derived from the initial PDB structure. This merged pharmacophore model contains all features that are present during the simulation and statistical information about the dynamics of the pharmacophore features. Based on the dynamics of the pharmacophore features we derive two distinctive feature patterns resulting in two different pharmacophore models for the analyzed system - the first model consists of features that are obtained from the PDB structure and the second uses two features that can only be derived from the molecular dynamics simulation. Both models can distinguish between active and decoy molecules in virtual screening. Our approach represents an objective way to add/remove features in pharmacophore models and can be of interest for the investigation of any naturally occurring system that relies on ligand-receptor interactions for its biological activity.