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Virtual screening

About: Virtual screening is a(n) research topic. Over the lifetime, 6834 publication(s) have been published within this topic receiving 177549 citation(s).

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Journal ArticleDOI
John J. Irwin1, Brian K. ShoichetInstitutions (1)
TL;DR: This paper has prepared a library of 727,842 molecules, each with 3D structure, using catalogs of compounds from vendors, and hopes that this database will bring virtual screening libraries to a wide community of structural biologists and medicinal chemists.

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Abstract: A critical barrier to entry into structure-based virtual screening is the lack of a suitable, easy to access database of purchasable compounds. We have therefore prepared a library of 727,842 molecules, each with 3D structure, using catalogs of compounds from vendors (the size of this library continues to grow). The molecules have been assigned biologically relevant protonation states and are annotated with properties such as molecular weight, calculated LogP, and number of rotatable bonds. Each molecule in the library contains vendor and purchasing information and is ready for docking using a number of popular docking programs. Within certain limits, the molecules are prepared in multiple protonation states and multiple tautomeric forms. In one format, multiple conformations are available for the molecules. This database is available for free download (http://zinc.docking.org) in several common file formats including SMILES, mol2, 3D SDF, and DOCK flexibase format. A Web-based query tool incorporating a molecular drawing interface enables the database to be searched and browsed and subsets to be created. Users can process their own molecules by uploading them to a server. Our hope is that this database will bring virtual screening libraries to a wide community of structural biologists and medicinal chemists.

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2,949 citations


Journal ArticleDOI
TL;DR: Key concepts and specific features of small-molecule–protein docking methods are reviewed, selected applications are highlighted and recent advances that aim to address the acknowledged limitations of established approaches are discussed.

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Abstract: Computational approaches that 'dock' small molecules into the structures of macromolecular targets and 'score' their potential complementarity to binding sites are widely used in hit identification and lead optimization Indeed, there are now a number of drugs whose development was heavily influenced by or based on structure-based design and screening strategies, such as HIV protease inhibitors Nevertheless, there remain significant challenges in the application of these approaches, in particular in relation to current scoring schemes Here, we review key concepts and specific features of small-molecule-protein docking methods, highlight selected applications and discuss recent advances that aim to address the acknowledged limitations of established approaches

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2,455 citations


Journal ArticleDOI
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.

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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.

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2,455 citations


Journal ArticleDOI
Alan L. Harvey1Institutions (1)
TL;DR: Various screening approaches are being developed to improve the ease with which natural products can be used in drug discovery campaigns, and data mining and virtual screening techniques are also being applied to databases of natural products.

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Abstract: Natural products have been the single most productive source of leads for the development of drugs. Over a 100 new products are in clinical development, particularly as anti-cancer agents and anti-infectives. Application of molecular biological techniques is increasing the availability of novel compounds that can be conveniently produced in bacteria or yeasts, and combinatorial chemistry approaches are being based on natural product scaffolds to create screening libraries that closely resemble drug-like compounds. Various screening approaches are being developed to improve the ease with which natural products can be used in drug discovery campaigns, and data mining and virtual screening techniques are also being applied to databases of natural products. It is hoped that the more efficient and effective application of natural products will improve the drug discovery process.

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1,526 citations


Book
10 Apr 1992-
TL;DR: The Organic Chemistry of Drug Design and Drug Action, Third Edition, represents a unique approach to medicinal chemistry based on physical organic chemical principles and reaction mechanisms that rationalize drug action, which allows the reader to extrapolate those core principles and mechanisms to many related classes of drug molecules.

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Abstract: The Organic Chemistry of Drug Design and Drug Action, Third Edition, represents a unique approach to medicinal chemistry based on physical organic chemical principles and reaction mechanisms that rationalize drug action, which allows the reader to extrapolate those core principles and mechanisms to many related classes of drug molecules. This new edition reflects significant changes in the process of drug design over the last decade. It preserves the successful approach of the previous editions while including significant changes in format and coverage. New to this edition: * Updates to all chapters, including new examples and references* Chapter 1 (Introduction): Completely rewritten and expanded as an overview of topics discussed in detail throughout the book* Chapter 2 (Lead Discovery and Lead Modification): Sections on sources of compounds for screening including library collections, virtual screening, and computational methods, as well as hit-to-lead and scaffold hopping; expanded sections on sources of lead compounds, fragment-based lead discovery, and molecular graphics; and deemphasized solid-phase synthesis and combinatorial chemistry* Chapter 3 (Receptors): Drug-receptor interactions, cation-? and halogen bonding; atropisomers; case history of the insomnia drug suvorexant* Chapter 4 (Enzymes): Expanded sections on enzyme catalysis in drug discovery and enzyme synthesis* Chapter 5 (Enzyme Inhibition and Inactivation): New case histories: * for competitive inhibition, the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib and Abelson kinase inhibitor, imatinib* for transition state analogue inhibition, the purine nucleoside phosphorylase inhibitors, forodesine and DADMe-ImmH, as well as the mechanism of the multisubstrate analog inhibitor isoniazid* for slow, tight-binding inhibition, the dipeptidyl peptidase-4 inhibitor, saxagliptin* Chapter 7 (Drug Resistance and Drug Synergism): This new chapter includes topics taken from two chapters in the previous edition, with many new examples* Chapter 8 (Drug Metabolism): Discussions of toxicophores and reactive metabolites* Chapter 9 (Prodrugs and Drug Delivery Systems): Discussion of antibody-drug conjugates

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1,475 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202214
2021739
2020663
2019521
2018452
2017449

Top Attributes

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Topic's top 5 most impactful authors

Gisbert Schneider

68 papers, 3.2K citations

Gerhard Wolber

43 papers, 2.7K citations

Thierry Langer

36 papers, 1.5K citations

Jürgen Bajorath

35 papers, 4.2K citations

Hwangseo Park

29 papers, 573 citations