Journal ArticleDOI
Novel method for generating structure-based pharmacophores using energetic analysis.
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TLDR
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.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 pr...read more
Citations
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Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments
TL;DR: It is shown that database enrichment is improved with proper preparation and that neglecting certain steps of the preparation process produces a systematic degradation in enrichments, which can be large for some targets.
Journal ArticleDOI
FRED Pose Prediction and Virtual Screening Accuracy
TL;DR: This analysis shows that most docking programs are effective overall but highly inconsistent, tending to do well on one system and poorly on the next, particularly when using a global enrichment metric (AUC).
Journal ArticleDOI
Challenges and advances in computational docking: 2009 in review
TL;DR: This review addresses methodological developments that have occurred in the docking field in 2009, with a particular focus on the more difficult, and sometimes controversial, aspects of this promising computational discipline.
Journal ArticleDOI
Rapid shape-based ligand alignment and virtual screening method based on atom/feature-pair similarities and volume overlap scoring.
TL;DR: A new shape-based flexible ligand superposition and virtual screening method, Phase Shape, is shown to rapidly produce accurate 3D ligand alignments and efficiently enrich actives in virtual screening.
Journal ArticleDOI
Combination of ligand- and structure-based methods in virtual screening
TL;DR: Different strategies for integration of ligand- and structure-based molecular modelling methods which can be divided into sequential, parallel or hybrid approaches are described.
References
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Journal ArticleDOI
The Protein Data Bank
Helen M. Berman,John D. Westbrook,Zukang Feng,Gary L. Gilliland,Talapady N. Bhat,Helge Weissig,Ilya N. Shindyalov,Philip E. Bourne +7 more
TL;DR: The goals of the PDB are described, the systems in place for data deposition and access, how to obtain further information and plans for the future development of the resource are described.
Journal ArticleDOI
Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy.
Richard A. Friesner,Jay L. Banks,Robert B. Murphy,Thomas A. Halgren,Jasna Klicic,Daniel T. Mainz,Matthew P. Repasky,Eric H. Knoll,Mee Shelley,Jason K. Perry,David E. Shaw,Perry Francis,Peter S Shenkin +12 more
TL;DR: Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand to find the best docked pose using a model energy function that combines empirical and force-field-based terms.
Journal ArticleDOI
Development and validation of a genetic algorithm for flexible docking.
TL;DR: GOLD (Genetic Optimisation for Ligand Docking) is an automated ligand docking program that uses a genetic algorithm to explore the full range of ligand conformational flexibility with partial flexibility of the protein, and satisfies the fundamental requirement that the ligand must displace loosely bound water on binding.
Journal ArticleDOI
Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening.
Thomas A. Halgren,Robert B. Murphy,Richard A. Friesner,Hege S. Beard,Leah L. Frye,W. Thomas Pollard,Jay L. Banks +6 more
TL;DR: Comparisons to results for the thymidine kinase and estrogen receptors published by Rognan and co-workers show that Glide 2.5 performs better than GOLD 1.1, FlexX 1.8, or DOCK 4.01.
Journal ArticleDOI
Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein-Ligand Complexes
Richard A. Friesner,Robert B. Murphy,Matthew P. Repasky,Leah L. Frye,Jeremy R. Greenwood,Thomas A. Halgren,Paul C. Sanschagrin,Daniel T. Mainz +7 more
TL;DR: Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.