8did: Difference between revisions

← Older edit

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 12: / Line 12: @@
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-Antiviral therapeutics to treat SARS-CoV-2 are needed to diminish the morbidity of the ongoing COVID-19 pandemic. A well-precedented drug target is the main viral protease (M(Pro) ), which is targeted by an approved drug and by several investigational drugs. Emerging viral resistance has made new inhibitor chemotypes more pressing. Adopting a structure-based approach, we docked 1.2 billion non-covalent lead-like molecules and a new library of 6.5 million electrophiles against the enzyme structure. From these, 29 non-covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC(50) of 29 muM and 20 muM, respectively. Several series were optimized, resulting in low micromolar inhibitors. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. While the new chemotypes may aid further optimization of M(Pro) inhibitors for SARS-CoV-2, the modest success rate also reveals weaknesses in our approach for challenging targets like M(Pro) versus other targets where it has been more successful, and versus other structure-based techniques against M(Pro) itself. This article is protected by copyright. All rights reserved.
+Antiviral therapeutics to treat SARS-CoV-2 are needed to diminish the morbidity of the ongoing COVID-19 pandemic. A well-precedented drug target is the main viral protease (M(Pro) ), which is targeted by an approved drug and by several investigational drugs. Emerging viral resistance has made new inhibitor chemotypes more pressing. Adopting a structure-based approach, we docked 1.2 billion non-covalent lead-like molecules and a new library of 6.5 million electrophiles against the enzyme structure. From these, 29 non-covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC(50) of 29 and 20 muM, respectively. Several series were optimized, resulting in low micromolar inhibitors. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. While the new chemotypes may aid further optimization of M(Pro) inhibitors for SARS-CoV-2, the modest success rate also reveals weaknesses in our approach for challenging targets like M(Pro) versus other targets where it has been more successful, and versus other structure-based techniques against M(Pro) itself.
-Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors.,Fink EA, Bardine C, Gahbauer S, Singh I, Detomasi T, White K, Gu S, Wan X, Chen J, Ary B, Glenn I, O'Connell J, O'Donnell H, Fajtova P, Lyu J, Vigneron S, Young NJ, Kondratov IS, Alisoltani A, Simons LM, Lorenzo-Redondo R, Ozer EA, Hultquist JF, O'Donoghue AJ, Moroz Y, Taunton J, Renslo AR, Irwin JJ, Garcia-Sastre A, Shoichet BK, Craik CS Protein Sci. 2023 Jun 24:e4712. doi: 10.1002/pro.4712. PMID:37354015<ref>PMID:37354015</ref>
+Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors.,Fink EA, Bardine C, Gahbauer S, Singh I, Detomasi TC, White K, Gu S, Wan X, Chen J, Ary B, Glenn I, O'Connell J, O'Donnell H, Fajtova P, Lyu J, Vigneron S, Young NJ, Kondratov IS, Alisoltani A, Simons LM, Lorenzo-Redondo R, Ozer EA, Hultquist JF, O'Donoghue AJ, Moroz YS, Taunton J, Renslo AR, Irwin JJ, Garcia-Sastre A, Shoichet BK, Craik CS Protein Sci. 2023 Aug;32(8):e4712. doi: 10.1002/pro.4712. PMID:37354015<ref>PMID:37354015</ref>
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>