title: Novel method for generating structure-based pharmacophores using energetic analysis.
abstract: We describe a novel method to develop energetically optimized, structure-based pharmacophores for use in rapid in silico screening. The method combines pharmacophore perception and database screening with protein-ligand energetic terms computed by the Glide XP scoring function to rank the importance of pharmacophore features. We derive energy-optimized pharmacophore hypotheses for 30 pharmaceutically relevant crystal structures and screen a database to assess the enrichment of active compounds. The method is compared to three other approaches: (1) pharmacophore hypotheses derived from a systematic assessment of receptor-ligand contacts, (2) Glide SP docking, and (3) 2D ligand fingerprint similarity. The method developed here shows better enrichments than the other three methods and yields a greater diversity of actives than the contact-based pharmacophores or the 2D ligand similarity. Docking produces the most cases (28/30) with enrichments greater than 10.0 in the top 1% of the database and on average produces the greatest diversity of active molecules. The combination of energy terms from a structure-based analysis with the speed of a ligand-based pharmacophore search results in a method that leverages the strengths of both approaches to produce high enrichments with a good diversity of active molecules.
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, 29th Floor, New York, New York 10036, USA. Noeris.Salam@Schrodinger.com
authors.forename: Noeris K
authors.initials: NK
authors.lastname: Salam
authors.forename: Roberto
authors.initials: R
authors.lastname: Nuti
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
mesh_terms: D019295:Computational Biology; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011506:Proteins