## 2 Materials and Methods
### Molecular Dynamics Simulation  
According to the results of the molecular docking analysis and ADMET evaluations, three different complexes were submitted to all-atom molecular dynamics simulations: HSP90_L1, HSP90_L2, and HSP90_MEY as a reference complex. The three simulations were run at 300 ns with the CHARMM36 force field from the Gromacs-2023 program. The molecular topology data of the identified inhibitors and the reference drug (MEY) were derived from the SwissParam platform ([[http://swissparam.ch/](http://swissparam.ch/)]([http://swissparam.ch/](http://swissparam.ch/)) accessed on 10 June2024) [22]. Additionally, the editconf function was used to create a simulation box on the complex with an absolute minimum distance of 10 A to any wall. Furthermore, the intermolecular potential using the TIP3P water model was utilized to fill the box with solvent molecules with the application of the \(gmx\) solvate command [22]. The charge for each system was neutralized by the addition of (Na+, Cl-) ions. The steepest descent technique (1000 ps) for protein configuration was used to minimize the energy. For energy minimization, set nsteps to 50,000 were modified to an energy step size (emstep) of 0.01 [23]. NVT equilibration was conducted at 300 K for 500 ps using a V-rescale thermostat. The NPT was then adjusted for 100 ps using a Berenson pressure-coupling system and a coupling value of 2.0 ps. Finally, the MD simulation was performed at 300 ns for each system, using nsteps of 150,000,000 specified in the md.mdp data.  
We analyzed the MD simulation results to gain understanding of the compactness, flexibility, and stability of the complexes that were produced. While the root mean square fluctuation (RMSF) was used to evaluate the flexibility of all residues, the root mean square deviation (RMSD) was used to determine the structural change of each system during 300 ns of simulation. Each complex's compactness was ascertained using the radius of gyration (Rg). In order to assess the overall stability of the complexes that were generated, we also calculated the solvent-accessible surface area (SASA). To analyze the simulated trajectories, the Grace program ([[http://plasma-gate.weizmann.ac.il/Grace/](http://plasma-gate.weizmann.ac.il/Grace/)]([http://plasma-gate.weizmann.ac.il/Grace/](http://plasma-gate.weizmann.ac.il/Grace/)) accessed on 12 June 2024) was used. Lastly, we used the free energy landscape (FEL) to investigate the systems' molecular stability.  
Calculating Binding Free Energy  
The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) is a popular approach for estimating a protein-ligand complex's binding free energy. The MM-PBSA binding free energy (\(\Delta\)G\({}_{\text{bind}}\)) evaluation was performed using the g_mmpbsa tool's specified technique. The binding free energy was computed in the following way:  
\[\Delta\text{G}_{\text{bind}}=\text{G}_{\text{complex}}-(\text{G}_{\text{ protein}}+\text{G}_{\text{ligand}})\]  
Here, G\({}_{\text{complex}}\) indicates the native protein's binding energy, whereas G\({}_{\text{protein}}\) and G\({}_{\text{ligand}}\) reflect the protein's and ligand's binding energies.