Structure-based design of ligands of the m6A-RNA reader YTHDC1
| Title | Structure-based design of ligands of the m6A-RNA reader YTHDC1 |
| Publication Type | Journal Article |
| Year of Publication | 2022 |
| Authors | Li Y., Bedi R.K, Nai F., von Roten V., Dolbois A., Zálešák F., Nachawati R., Huang D., Caflisch A. |
| Journal | European Journal of Medicinal Chemistry Reports |
| Volume | 5 |
| Pagination | 100057 |
| Date Published | 2022/08/01/ |
| Type of Article | Research Article |
| ISBN Number | 2772-4174 |
| Keywords | epitranscriptomics, Fragment-based drug discovery (FBDD), Molecular docking, molecular dynamics, RNA epigenetics, X-ray crystallography, YTHDC1 binders |
| Abstract | 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. |
| URL | https://www.sciencedirect.com/science/article/pii/S2772417422000292 |
| DOI | 10.1016/j.ejmcr.2022.100057 |
| pubindex | 0278 |
| Alternate Journal | Eur. J. Med. Chem. Rep. |
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