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
Rapid approach to complex boronic acids.
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TL;DR: The synthesis of large libraries of boronic acid derivatives based on multiple chemistries and building blocks using acoustic dispensing technology was performed on a nanomole scale with high synthesis success rates and the discovery of a protease inhibitor underscores the usefulness of the approach.
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TL;DR: In this article, the bioactive phytocompounds from traditional antiviral herb Houttuynia cordata were identified as potential inhibitors for three main replication proteins of SARS-CoV-2, namely, Main protease (Mpro), Papain-Like proteases (PLpro), and ADP ribose phosphatase (ADRP) which control the replication process.
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Computational polypharmacology analysis of the heat shock protein 90 interactome.
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TL;DR: Stereoselective production of 17,18-EpETE by each CYP isoform was confirmed, and molecular modeling indicated that chiral differences stem from different EPA binding conformations in the catalytic domains of respective CYP enzymes.
References
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Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy.
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