Automated Pharmacophore Generation and Its Use in Virtual Screening
One potential approach for using molecular dynamics (MD) trajectories of proteins or protein–small molecule complexes as starting points for virtual screening and de novo design relies on the use of pharmacophores. In the case of a single structure, pharmacophore generation is usually performed manually, which is time-consuming and subjective, and therefore not easily applied to the many structures coming from an MD trajectory. Here we describe a fast and automated procedure that we have developed to generate pharmacophores from either holo- or apo-protein structures. We demonstrate the usefulness of such automatically generated pharmacophores using the DUD-E virtual screening validation set in combination with our in-house virtual screening protocol. We found that our pharmacophore-based virtual screening approach not only greatly outperforms other pharmacophore-based methods for which results are available, but that it also shows performance comparable to the best-available docking methods (judged according to standard metrics). We also attained a significantly higher early enrichment compared to docking, which should provide a practical advantage in drug discovery applications.