Journal ArticleDOI
Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments
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TLDR
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.Abstract:
Structure-based virtual screening plays an important role in drug discovery and complements other screening approaches. In general, protein crystal structures are prepared prior to docking in order to add hydrogen atoms, optimize hydrogen bonds, remove atomic clashes, and perform other operations that are not part of the x-ray crystal structure refinement process. In addition, ligands must be prepared to create 3-dimensional geometries, assign proper bond orders, and generate accessible tautomer and ionization states prior to virtual screening. While the prerequisite for proper system preparation is generally accepted in the field, an extensive study of the preparation steps and their effect on virtual screening enrichments has not been performed. In this work, we systematically explore each of the steps involved in preparing a system for virtual screening. We first explore a large number of parameters using the Glide validation set of 36 crystal structures and 1,000 decoys. We then apply a subset of protocols to the DUD database. We show 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. We provide examples illustrating the structural changes introduced by the preparation that impact database enrichment. While the work presented here was performed with the Protein Preparation Wizard and Glide, the insights and guidance are expected to be generalizable to structure-based virtual screening with other docking methods.read more
Citations
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The garlic compound ajoene covalently binds vimentin, disrupts the vimentin network and exerts anti-metastatic activity in cancer cells.
Catherine H. Kaschula,Rosanna Tuveri,Ellen Ngarande,Kevin Dzobo,Kevin Dzobo,Christopher B. Barnett,Daniel A. Kusza,Lisa M. Graham,Arieh A. Katz,Mohamed Suhail Rafudeen,M. Iqbal Parker,Roger Hunter,Georgia Schäfer +12 more
TL;DR: Ajoene inhibited the invasion and migration of both cancer cell lines which was found to be dependent on the presence of vimentin, and contributes to the anti-metastatic activity of ajoene in cancer cells.
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Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations
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TL;DR: The binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition is estimated, based on five different crystal structures, with varying and rather poor results.
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Tryptamine-based derivatives as Transient Receptor Potential Melastatin type-8 (TRPM8) channel modulators
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Synthesis, X-ray crystallographic study and molecular docking of new α-sulfamidophosphonates: POM analyses of their cytotoxic activity
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TL;DR: A series of novel α-sulfamidophosphonate derivatives was rationally designed and synthesized following the principle of the superposition of bioactive substructures by the combination of sulfonamide, aldehyde and triethylphosphite.
References
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TL;DR: The Protein Data Bank is a computer-based archival file for macromolecular structures that stores in a uniform format atomic co-ordinates and partial bond connectivities, as derived from crystallographic studies.
Journal ArticleDOI
Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy.
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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.
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