Encounter and React: Computer-Guided Design of Covalent Inhibitors
Peter Man-Un Ung1, Robert J DeVita2, Avner Schlessinger1
1Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Cell Chemical Biology
|January 19, 2019
Summary
Researchers designed novel covalent inhibitors targeting MKK7 to modulate the JNK-Jun pathway. This strategy offers enhanced selectivity and extended residence time for potential therapeutic applications.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- Covalent inhibitors offer advantages in selectivity and prolonged target engagement.
- The JNK-Jun pathway is implicated in various cellular processes and diseases.
- Developing targeted modulators of this pathway is therapeutically relevant.
Purpose of the Study:
- To design and develop novel covalent inhibitors targeting MKK7.
- To modulate the JNK-Jun signaling pathway using these inhibitors.
- To explore a new strategy for therapeutic discovery.
Main Methods:
- Computational modeling and design of covalent inhibitors.
- Experimental validation of inhibitor activity and selectivity.
- Assessment of JNK-Jun pathway modulation.
Main Results:
- Successful design and synthesis of MKK7 covalent inhibitors.
- Demonstrated modulation of the JNK-Jun pathway.
- Achieved optimal selectivity and extended residence time.
Conclusions:
- Covalent inhibition of MKK7 is a viable strategy to modulate the JNK-Jun pathway.
- The developed inhibitors show promise for therapeutic development.
- This approach represents an emerging strategy in therapeutic discovery.
Related Concept Videos
01:29Covalent Bonds
162.1K
Overview
162.1K
01:08Covalent Bonds
10.8K
Overview
When two atoms share electrons to complete their valence shells, they create a covalent bond. An atom's electronegativity—the force with which shared electrons are pulled towards an atom—determines how the electrons are shared. Molecules formed with covalent bonds can be either polar or nonpolar. Atoms with similar electronegativities form nonpolar covalent bonds; the electrons are shared equally. Atoms with different electronegativities share electrons unequally,...
When two atoms share electrons to complete their valence shells, they create a covalent bond. An atom's electronegativity—the force with which shared electrons are pulled towards an atom—determines how the electrons are shared. Molecules formed with covalent bonds can be either polar or nonpolar. Atoms with similar electronegativities form nonpolar covalent bonds; the electrons are shared equally. Atoms with different electronegativities share electrons unequally,...
10.8K
02:18Network Covalent Solids
16.2K
Network covalent solids contain a three-dimensional network of covalently bonded atoms as found in the crystal structures of nonmetals like diamond, graphite, silicon, and some covalent compounds, such as silicon dioxide (sand) and silicon carbide (carborundum, the abrasive on sandpaper). Many minerals have networks of covalent bonds.
To break or to melt a covalent network solid, covalent bonds must be broken. Because covalent bonds are relatively strong, covalent network solids are typically...
To break or to melt a covalent network solid, covalent bonds must be broken. Because covalent bonds are relatively strong, covalent network solids are typically...
16.2K
02:04Covalently Linked Protein Regulators
9.6K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
9.6K
02:04Covalently Linked Protein Regulators
2.0K
2.0K
02:46Covalent Bonding and Lewis Structures
61.3K
Compared to ionic bonds, which results from the transfer of electrons between metallic and nonmetallic atoms, covalent bonds result from the mutual attraction of atoms for a “shared” pair of electrons.
61.3K