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.