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.

Long-range Electrostatic Complementarity Governs Substrate Recognition by Human Chymotrypsin C, a Key Regulator of Digestive Enzyme Activation

“…Substrates were docked into the binding site of CTRC using Glide extra precision (XP) (Glide, version 5.6, Schrödinger, LLC); molecular conformations were sampled using methods described previously (32). A structure-based pharmacophore score was generated from the optimized, best scoring pose for each substrate ligand based on the descriptors from the Glide XP score using an established approach (31,33,34). The energetic value assigned to each pharmacophore feature was calculated using Phase (Phase, version 3.2, Schrödinger, LLC) as the sum of the Glide XP contributions of the atoms comprising the site.…”

“…The energetic value assigned to each pharmacophore feature was calculated using Phase (Phase, version 3.2, Schrödinger, LLC) as the sum of the Glide XP contributions of the atoms comprising the site. Overall dockings at the active site were quantified and ranked on the basis of these energetic terms (33,34). To account for protein flexibility and lessen the effects of minor steric clashes, excluded volumes spheres corresponding to 80% of the van der Waals atomic radii were created for all CTRC atoms within 6 Å of each substrate or mutagenized residue modeled.…”

“…To account for protein flexibility and lessen the effects of minor steric clashes, excluded volumes spheres corresponding to 80% of the van der Waals atomic radii were created for all CTRC atoms within 6 Å of each substrate or mutagenized residue modeled. A minimum of two poses per substrate, chosen for a combination of best-scoring features, was selected for visual and energetic comparison (31,33,34).…”

Human Rab8b Protein as a Cancer Target - An In Silico Study

“…OPLS_2005 (Optimized potentials for liquid simulations) force field [24,25]. The quality of the generated model is evaluated by a series of tests for its internal consistency and reliability.…”

Discovery and Optimization of Inhibitors of DNA Methyltransferase as Novel Drugs for Cancer Therapy

“…Using the energy optimized hypothesis, 'epharmacophore' method (Salam et al, 2009) the pharmacophore model was developed based on the scores and predicted binding modes of 14 known DNMT1 inhibitors docked with a homology model of DNMT1. Fig.…”