Structure-based design of ligands of the m 6 A-RNA reader YTHDC1

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 simulatio...

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Bibliographic Details
Published in:European journal of medicinal chemistry reports 2022, Vol.5
Main Authors: Li, Yaozong, Bedi, Rajiv Kumar, Nai, Francesco, von Roten, Valentin, Dolbois, Aymeric, Zálešák, František, Nachawati, Raed, Huang, Danzhi, Caflisch, Amedeo
Format: Article
Language:English
Subjects:
Fragment-based drug discovery (FBDD)
Molecular docking
Molecular dynamics
RNA epigenetics
X-ray crystallography
YTHDC1 binders
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Summary: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.
ISSN:2772-4174
2772-4174
DOI:10.1016/j.ejmcr.2022.100057