## 3 Results and Discussion
### Analysis from MD Simulations  
MD simulations were performed on YTHDC1 in a complex with 6 MZ. The ligand was observed to stay inside the pocket within a 100-ns simulation, suggesting that the m6A alone binds to YTHDC1, although it is part of the RNA complex [27]. MD simulations were then conducted for the 15 protein-ligand complexes in Table 1 to investigate the compound's overall binding stability (Figure S3). The starting poses for the simulation studies were obtained from the Geom-X docking experiment. The simulations were performed for 100 ns, and the information retrieved through trajectories was used to examine the conformational stability of the complexes. During the simulation, the \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**No** & **Molecule** & **Hydrogen Bonds** & \begin{tabular}{c} **Autodock Score** \\ **(kcal/mol)** \\ \end{tabular} & \
\begin{tabular}{c} **GeomX Score** \\ **(kcal/mol)** \\ \end{tabular} &
\begin{tabular}{c} **H hydrogen Bonding Residues** \\ \end{tabular} \\ \hline
1 & ZINC65274016 & 4 & \(-\)10.77 & \(-\)10.94 & Asn367, Ser378, Asn363, Arg475 \\
2 & ZINC82121447 & 2 & \(-\)9.13 & \(-\)10.20 & Ser378, Asp476 \\
3 & ZINC024121416 & 2 & \(-\)8.95 & \(-\)10.27 & Asn363, Arg475 \\
4 & ZINC12780673 & 3 & \(-\)8.90 & \(-\)9.87 & Asn367, Ser378, Arg475 \\
5 & ZINC64755558 & 4 & \(-\)8.90 & \(-\)10.16 & Asn367, Ser378, Asn363, Asp476 \\
6 & ZINC00807117 & 4 & \(-\)8.73 & \(-\)9.84 & Asn367, Ser378, Asn363, Arg475 \\
7 & ZINC91526763 & 4 & \(-\)8.44 & \(-\)10.21 & Asn367, Asn363, Ser378, Asp476 \\
8 & ZINC01330611 & 2 & \(-\)8.43 & \(-\)9.94 & Asn367, Asn363 \\
9 & ZINC02170552 & 2 & \(-\)8.25 & \(-\)9.38 & Asn367, Asn363 \\
10 & ZINC06764561 & 3 & \(-\)8.23 & \(-\)9.77 & Asn367, Asn363, Ser378, Cys378 \\
11 & ZINC10763862 & 3 & \(-\)8.10 & \(-\)10.12 & Asn367, Ser378, Lys361 \\
12 & ZINC67726926 & 4 & \(-\)8.07 & \(-\)9.6 & Asn367, Asn363, Ser378, Asp476 \\
13 & ZINC65384150 & 4 & \(-\)7.89 & \(-\)10.29 & Asn367, Asn363, Ser378, Asp476 \\
14 & ZINC83841263 & 3 & \(-\)7.87 & \(-\)11.03 & Asn367, Ser378, Arg475 \\
15 & ZINC67981980 & 3 & \(-\)7.56 & \(-\)10.24 & Asn363, Asn367, Ser378 \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Binding affinities of the studied small molecules with the target protein (See Figure S8 for the structures of the listed molecules). Figure 3: (**A–E**) The 3D surface structure with 3D and 2D interactions for the top five small molecules (ZINC65274016, ZINC82121447, ZINC02412146, ZINC12780673, and ZINC64755558) identified as potential inhibitors of the YTHDC1 protein. RMSD of the protein backbone atoms was computed to evaluate the system stability. For the production run, RMSDs of both the ligand and the protein backbone were calculated and plotted for all systems. The interaction patterns were found to maintain the docking-predicted hydrogen bonds and hydrophobic contacts throughout the MD simulations. For ZINC82121447, the ligand flipped around 40 ns, and the part outside of the pocket was found to enter in the pocket of YTHDC1. However, ZINC82121447 remained inside the pocket during 100 ns simulation, as seen from the distance between the center of mass (COM) of the protein and the COM of the ligand (Figure S5). Two compounds, ZINC58341263 and ZINC91526763, were observed by visual inspections to get out of the pocket during the simulation time and showed large RMSDs and distances between the COMs of protein and ligand (Figures S3 and S6). The obtained low-RMSD values for the top five protein-ligand complexes (Figure 4) showed that the ligands and protein backbone were structurally stable. The average RMSD of ligand atoms (protein backbone atoms) was computed to be 0.20 (0.22), 0.15 (0.12), 0.21 (0.12), 0.13 (0.12), and 0.13 (0.15) nm for ZINC65274016, ZINC82121447, ZINC02412146, ZINC12780673, and ZINC64755558, respectively. Moreover, the presence of plateaus in RMSD curves of almost all complexes except ZINC58341263 and ZINC12780673 confirmed the stability throughout the simulations.