New Electrophiles and Strategies for Mechanism-Based and Targeted Covalent Inhibitor Design

Biochemistry ◽  
2019 ◽  
Vol 58 (52) ◽  
pp. 5234-5244 ◽  
Author(s):  
Sneha Ray ◽  
Andrew S. Murkin
Keyword(s):  
Inhibitor Design ◽  
Covalent Inhibitor

scholarly journals The role of quantum chemistry in covalent inhibitor design

2021 ◽  
Author(s):  
Levente M. Mihalovits ◽  
György G. Ferenczy ◽  
György M. Keserű
Keyword(s):  
Quantum Chemistry ◽  
Inhibitor Design ◽  
Covalent Inhibitor

Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: A Reactive Group for Targeted Covalent Inhibitor Design

2021 ◽  
Author(s):  
Tuğçe G. Erbay ◽  
Daniel P. Dempe ◽  
Bhaskar Godugu ◽  
Peng Liu ◽  
Kay M. Brummond
Keyword(s):  
Inhibitor Design ◽  
Reactive Group ◽  
Thiol Reactivity ◽  
Covalent Inhibitor

Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo

2021 ◽  
Author(s):  
Christian Dubiella ◽  
Benika J. Pinch ◽  
Kazuhiro Koikawa ◽  
Daniel Zaidman ◽  
Evon Poon ◽  
...  
Keyword(s):  
Covalent Inhibitor

Metabolic disposition of the EGFR covalent inhibitor furmonertinib in humans

2021 ◽  
Author(s):  
Jian Meng ◽  
Hua Zhang ◽  
Jing-jing Bao ◽  
Zhen-dong Chen ◽  
Xiao-yun Liu ◽  
...  
Keyword(s):  
Covalent Inhibitor ◽  
Metabolic Disposition

scholarly journals Identification of pyrogallol as a warhead in design of covalent inhibitors for the SARS-CoV-2 3CL protease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haixia Su ◽  
Sheng Yao ◽  
Wenfeng Zhao ◽  
Yumin Zhang ◽  
Jia Liu ◽  
...  
Keyword(s):  
Theoretical Calculations ◽  
Cysteine Proteinase ◽  
Covalent Binding ◽  
Food Sources ◽  
Binding Mechanism ◽  
Covalent Inhibitors ◽  
Catalytic Cysteine ◽  
3Cl Protease ◽  
Covalent Ligands ◽  
Covalent Inhibitor

AbstractThe ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CLpro) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CLpro. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLpros, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.

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