Structure-based design of ligands of the m6A-RNA reader YTHDC1

TitleStructure-based design of ligands of the m6A-RNA reader YTHDC1
Publication TypeJournal Article
Year of Publication2022
AuthorsLi Y., Bedi R.K, Nai F., von Roten V., Dolbois A., Zálešák F., Nachawati R., Huang D., Caflisch A.
JournalEuropean Journal of Medicinal Chemistry Reports
Date Published2022/08/01/
Type of ArticleResearch Article
ISBN Number2772-4174
Keywordsepitranscriptomics, Fragment-based drug discovery (FBDD), Molecular docking, molecular dynamics, RNA epigenetics, X-ray crystallography, YTHDC1 binders

We report new chemical entities for disrupting the interactions between N6-methyladenosine (m6A) mRNA and its reader YT521-B homology-domain-containing protein 1 (YTHDC1). High-throughput docking was used to screen commercially available databases of small molecules, and molecular dynamics simulations were employed to evaluate the binding stability of m6A nucleotide analogues. The poses of 25 fragment-like new binders were confirmed by X-ray crystallography. The structure-based merging of two weak fragments resulted in a ligand-efficient binder (compound 6) which shows an equilibrium dissociation constant of 1.7 ​μM in isothermal titration calorimetry measurements and a ligand efficiency value of 0.66 ​kcal ​mol−1 nHA−1.



Alternate JournalEur. J. Med. Chem. Rep.