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10.1038/s41467-021-23443-y http://scihub22266oqcxt.onion/10.1038/s41467-021-23443-y 34045440!8159961!34045440     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Nat+Commun 2021 ; 12 (1): 3201 Nephropedia Template TP {{tp|p=34045440|t=2021. Exploring protein hotspots by optimized fragment pharmacophores |pdf=|usr=}}{{34045440}} gab.com Text Exploring protein hotspots by optimized fragment pharmacophores JO: Nat Commun http://www.kidney.de/pget.php?&tw=1&pmid=34045440 #FOAvip Fragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pharmacophores, the most general concept of representing drug-target interactions with the theory of protein hotspots, to develop a design protocol for fragment libraries. The SpotXplorer approach compiles small fragment libraries that maximize the coverage of experimentally confirmed binding pharmacophores at the most preferred hotspots. The efficiency of this approach is demonstrated with a pilot library of 96 fragment-sized compounds (SpotXplorer0) that is validated on popular target classes and emerging drug targets. Biochemical screening against a set of GPCRs and proteases retrieves compounds containing an average of 70% of known pharmacophores for these targets. More importantly, SpotXplorer0 screening identifies confirmed hits against recently established challenging targets such as the histone methyltransferase SETD2, the main protease (3CLPro) and the NSP3 macrodomain of SARS-CoV-2. Twit Text FOAVip Exploring protein hotspots by optimized fragment pharmacophores ????Nat Commun http://www.kidney.de/pget.php?&tw=1&pmid=34045440 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=34045440 #FOAvip English Wikipedia <ref>{{Cite pmid|34045440}}</ref> Exploring protein hotspots by optimized fragment pharmacophores #MMPMID34045440 Bajusz D; Wade WS; Satala G; Bojarski AJ; Ilas J; Ebner J; Grebien F; Papp H; Jakab F; Douangamath A; Fearon D; von Delft F; Schuller M; Ahel I; Wakefield A; Vajda S; Gerencser J; Pallai P; Keseru GM Nat Commun 2021[May]; 12 (1): 3201 PMID34045440show ga Fragment-based drug design has introduced a bottom-up process for drug development, with improved sampling of chemical space and increased effectiveness in early drug discovery. Here, we combine the use of pharmacophores, the most general concept of representing drug-target interactions with the theory of protein hotspots, to develop a design protocol for fragment libraries. The SpotXplorer approach compiles small fragment libraries that maximize the coverage of experimentally confirmed binding pharmacophores at the most preferred hotspots. The efficiency of this approach is demonstrated with a pilot library of 96 fragment-sized compounds (SpotXplorer0) that is validated on popular target classes and emerging drug targets. Biochemical screening against a set of GPCRs and proteases retrieves compounds containing an average of 70% of known pharmacophores for these targets. More importantly, SpotXplorer0 screening identifies confirmed hits against recently established challenging targets such as the histone methyltransferase SETD2, the main protease (3CLPro) and the NSP3 macrodomain of SARS-CoV-2. |Animals[MESH] |Cell Survival[MESH] |Chlorocebus aethiops[MESH] |Computational Chemistry[MESH] |Coronavirus 3C Proteases/*chemistry[MESH] |Coronavirus Papain-Like Proteases/*chemistry[MESH] |Crystallography, X-Ray[MESH] |Databases, Protein[MESH] |Drug Design[MESH] |Drug Development/*methods[MESH] |Drug Discovery/*methods[MESH] |HEK293 Cells[MESH] |High-Throughput Screening Assays/*methods[MESH] |Histone-Lysine N-Methyltransferase/*chemistry[MESH] |Humans[MESH] |Hydrogen Bonding[MESH] |Hydrophobic and Hydrophilic Interactions[MESH] |Ligands[MESH] |Protein Binding[MESH] |Receptors, G-Protein-Coupled/chemistry[MESH] |SARS-CoV-2/chemistry/genetics[MESH] |Small Molecule Libraries[MESH]Exploring protein hotspots by optimized fragment pharmacophores (epmc).pdf DeepDyve Pubget Overpricing