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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Journal ArticleDOI
Molecular Dynamics Simulation for All.
TL;DR: The types of information molecular dynamics simulations can provide and the ways in which they typically motivate further experimental work are described.
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A Robust and Accurate Tight-Binding Quantum Chemical Method for Structures, Vibrational Frequencies, and Noncovalent Interactions of Large Molecular Systems Parametrized for All spd-Block Elements (Z = 1–86)
TL;DR: The accuracy of the method, called Geometry, Frequency, Noncovalent, eXtended TB (GFN-xTB), is extensively benchmarked for various systems in comparison with existing semiempirical approaches, and the method is applied to a few representative structural problems in chemistry.
Journal ArticleDOI
Structure-based virtual screening for drug discovery: principles, applications and recent advances.
TL;DR: The principles and applications of Virtual Screening (VS) within the context of SBDD are examined and different procedures ranging from the initial stages of the process that include receptor and library pre-processing, to docking, scoring and post-processing of topscoring hits are examined.
Journal ArticleDOI
Comprehensive evaluation of ten docking programs on a diverse set of protein-ligand complexes: the prediction accuracy of sampling power and scoring power.
TL;DR: Overall, the ligand binding poses could be identified in most cases by the evaluated docking programs but the ranks of the binding affinities for the entire dataset could not be well predicted by most docking programs.
Journal ArticleDOI
Characterization and engineering of a plastic-degrading aromatic polyesterase
Harry P. Austin,Mark D. Allen,Bryon S. Donohoe,Nicholas A. Rorrer,Fiona L. Kearns,Rodrigo L. Silveira,Rodrigo L. Silveira,Benjamin C. Pollard,Graham Dominick,Ramona Duman,Kamel El Omari,Vitaliy Mykhaylyk,Armin Wagner,William E. Michener,Antonella Amore,Munir S. Skaf,Michael F. Crowley,Alan W. Thorne,Christopher W. Johnson,H. Lee Woodcock,John McGeehan,Gregg T. Beckham +21 more
TL;DR: 3D structure of a newly discovered enzyme that can digest highly crystalline PET, the primary material used in the manufacture of single-use plastic beverage bottles, in some clothing, and in carpets is characterized and it is shown that PETase degrades another semiaromatic polyester, polyethylene-2,5-furandicarboxylate (PEF), which is an emerging, bioderived PET replacement with improved barrier properties.
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
Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function
Garrett M. Morris,David S. Goodsell,Robert Scott Halliday,Ruth Huey,William E. Hart,Richard K. Belew,Arthur J. Olson +6 more
TL;DR: It is shown that both the traditional and Lamarckian genetic algorithms can handle ligands with more degrees of freedom than the simulated annealing method used in earlier versions of AUTODOCK, and that the Lamarckia genetic algorithm is the most efficient, reliable, and successful of the three.
Journal ArticleDOI
The Protein Data Bank: a computer-based archival file for macromolecular structures.
Frances C. Bernstein,Thomas F. Koetzle,Graheme J. B. Williams,Edgar F. Meyer,Michael D. Brice,John R. Rodgers,O. Kennard,Takehiko Shimanouchi,Mitsuo Tasumi +8 more
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.
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.