In silico discovery of multi-target small molecules and efficient siRNA design to overcome drug resistance in breast cancer via local therapy

In this study, we designed an efficient siRNA for PKMYT1 gene knockdown and evaluated the binding affinity of various natural small molecules to key proteins associated with breast cancer through molecular docking and molecular dynamics (MD) simulations. Subsequently, among these molecules, The small molecule, SCHEMBL7562664, was introduced as a “golden ligand” that showed potent multi‐target activity as an antagonist for aromatase, estrogen receptor α, HER2, and PARP10, and as an agonist for MT2 and STING. Next, MD simulations of six protein‐ golden ligand complexes (PDB IDs: 4QXQ, 5GS4, 5JL6, 5LX6, 6ME6, and 7PCD), performed with GROMACS over 100 ns at 298.15 K, provided valuable information about their structural dynamics. Analysis of the radius of gyration (Rg) revealed that, while five complexes (7PCD, 5GS4, 5LX6, 4QXQ, and 5JL6) maintained compact structures (Rg between 1.7 and 2.3 nm), the 6ME6 complex exhibited a more extended and flexible conformation (average Rg ∼3.4 nm). Complementary RMSD analysis confirmed that most complexes rapidly stabilized with minimal deviations (generally <0.3 nm), whereas the 6ME6 complex showed higher variability, reaching up to 0.67 nm. Furthermore, Binding free energy calculations using MM-GBSA and PBSA methods further supported these findings, with energies ranging from −21.45 ± 2.28 kcal/mol (5LX6) to −39.79 ± 1.34 kcal/mol (6ME6), indicating an optimal balance between intrinsic interactions and desolvation costs in the 6ME6 and 5JL6 systems. Based on DFT results, the golden ligand showed higher stability and lower reactivity compared to control ligands such as aromatase, tamoxifen, and dacomitinib, potentially leading to reduced off-target interactions and a more favorable safety profile. The integration of these data underscores the therapeutic potential of SCHEMBL7562664 as a multi-target agent for breast cancer, with promising pharmacokinetic properties that can be optimized for local treatment by incorporation into a 3D scaffold.