## 1 Introduction
Molecular dynamics (MD) simulations have been commonly applied to generate an ensemble of protein conformations, to investigate cryptic drug binding sites on the protein, and to optimize structures of protein-drug complexes [37]. It has also been demonstrated that MD simulations can be performed after the virtual screening to enhance the human selection process [38]. Molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) analysis has been employed to evaluate docking poses, determine structural stability, and estimate binding affinities [39]. Evaluating the absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties as early as possible is essential to determine the efficacy and safety of lead compounds as therapeutics. Various inhibitors have been identified in the ongoing quest to elucidate the regulatory functions of YTHDC1 and explore its potential as a therapeutic target. While these compounds offer promising avenues for drug development, understanding their interaction dynamics with YTHDC1 is imperative for optimizing their efficiency. We have extracted ligands co-crystallized with the YTHDC1 domain from the Protein Data Bank (PDB) to perform MD simulations and MM/PBSA analysis. These computational approaches offer robust avenues for probing the stability and binding affinities of these newly reported inhibitors, thus providing critical insights into their potential as effective modulators of YTHDC1. To the best of our knowledge, no approved inhibitors are presently known for YTH domain members. For METTL3, highly effective and specific inhibitors have been presented recently [40; 41; 42]. A few studies [43; 44; 45; 46] have reported small-molecule ligands with micromolar affinity for YTHDC1 m6A reader domain, and some [47; 48; 49; 50; 51; 52] have reported inhibitors for the m6A eraser FTO. For three YTHDF domains (YTHDF1/2/3), no ligands have been disclosed yet [53]. The uniqueness of this field and the role of YTHDC1 in the biological functions and in regulating the viral life cycle make YTHDC1 a fascinating target in the design of chemical probes and chemotherapy drugs. Thus, a complete understanding of the YTHDC1 molecular recognition mechanism is necessary. In the present study, a structure-based virtual screening analysis was performed to identify potential inhibitors for YTHDC1 from a database with a large number of small molecules using the molecular docking approach, MD simulations, MM/PBSA analysis, and ADMET profiling. Such a comprehensive investigation identified small molecules with high binding affinities for YTHDC1. Identified molecules exhibited favorable conformations and stable complex formation with YTHDC1, formed strong hydrogen bonds with SER378, ASN363, and ASN367 residues, and interacted with the aromatic cage of YTHDC1 through residues TRP377 and TRP428, and hydrophobic residue LEU439. The identified small molecules are predicted to demonstrate favorable pharmacokinetic and ADMET properties. These small molecules can be the foundation for designing and optimizing novel inhibitory substances and compounds against YTHDC1. The screening steps were carried out in a hierarchical way, as summarized in Figure 1.