Chemical Investigations Into the Biosynthesis of the Gymnastatin and Dankastatin Alkaloids

Chemical Science ◽

10.1039/d1sc02613e ◽

2021 ◽

Author(s):

Bingqi Tong ◽

Bridget Belcher ◽

Daniel Nomura ◽

Thomas Maimone

Keyword(s):

Natural Products ◽

Protein Function ◽

Bond Formation ◽

Covalent Bond ◽

Fungal Strain ◽

Fertile Ground ◽

Covalent Bond Formation

Electrophilic natural products have provided fertile ground for understanding how nature inhibits protein function using covalent bond formation. The fungal strain Gymnascella dankaliensis has provided an especially interesting collection of...

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Material Adhesion through Direct Covalent Bond Formation Assisted by Noncovalent Interactions

ACS Applied Polymer Materials ◽

10.1021/acsapm.1c00223 ◽

2021 ◽

Author(s):

Motofumi Osaki ◽

Tomoko Sekine ◽

Hiroyasu Yamaguchi ◽

Yoshinori Takashima ◽

Akira Harada

Keyword(s):

Noncovalent Interactions ◽

Bond Formation ◽

Covalent Bond ◽

Covalent Bond Formation

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Mechanism of Covalent Binding of Ibrutinib to Bruton’s Tyrosine Kinase revealed by QM/MM Calculations

10.26434/chemrxiv.13149893 ◽

2020 ◽

Author(s):

Angus Voice ◽

Gary Tresadern ◽

Rebecca Twidale ◽

Herman Van Vlijmen ◽

Adrian Mulholland

Keyword(s):

Tyrosine Kinase ◽

Covalent Binding ◽

Bond Formation ◽

Covalent Bond ◽

Covalent Modification ◽

Mechanistic Study ◽

Bruton’S Tyrosine Kinase ◽

Bruton's Tyrosine Kinase ◽

Covalent Inhibitors ◽

Covalent Bond Formation

Ibrutinib is the first covalent inhibitor of Bruton’s tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition is crucial for the design of safer and more selective covalent inhibitors that target BTK. There are questions surrounding the precise mechanism of covalent bond formation in BTK as there is no appropriate active site residue that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. To address this, we have investigated several mechanistic pathways of covalent modification of C481 in BTK by ibrutinib using QM/MM reaction simulations. The lowest energy pathway we identified involves a direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto-enol tautomerisation step (DG‡=10.5 kcal mol-1) to reach the inactivated BTK/ibrutinib complex. Our results represent the first mechanistic study of BTK inactivation by ibrutinib to consider multiple mechanistic pathways. These findings should aid in the design of covalent drugs that target BTK and related proteins.

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Supramolecular Assembly-Enabled Homochiral Polymerization of Short (dA)n Oligonucleotides

Chemical Communications ◽

10.1039/d1cc05420a ◽

2021 ◽

Author(s):

Sreejith Mangalath ◽

Suneesh C Karunakaran ◽

Gary Newnam ◽

Gary Schuster ◽

Nicholas Hud

Keyword(s):

Supramolecular Chemistry ◽

Bond Formation ◽

Supramolecular Assembly ◽

Covalent Bond ◽

Complex Mixtures ◽

Covalent Bond Formation

A goal of supramolecular chemistry is to create covalent polymers of precise composition and stereochemistry from complex mixtures by the reversible assembly of specific monomers prior to covalent bond formation....

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