Back to Search
Start Over
Free energy perturbation in the design of EED ligands as inhibitors of polycomb repressive complex 2 (PRC2) methyltransferase.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 May 01; Vol. 39, pp. 127904. Date of Electronic Publication: 2021 Mar 06. - Publication Year :
- 2021
-
Abstract
- Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.<br /> (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Subjects :
- Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Humans
Ligands
Microsomes, Liver chemistry
Microsomes, Liver metabolism
Molecular Structure
Polycomb Repressive Complex 2 metabolism
Purines chemical synthesis
Purines chemistry
Quantum Theory
Structure-Activity Relationship
Drug Design
Enzyme Inhibitors pharmacology
Polycomb Repressive Complex 2 antagonists & inhibitors
Purines pharmacology
Thermodynamics
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 39
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 33684441
- Full Text :
- https://doi.org/10.1016/j.bmcl.2021.127904