## 4 Discussion  
In this study, we aimed to identify _N-aryl-benzimidazole_ analogs as potential inhibitors of the HSP90 protein, a chaperone involved in multiple signaling pathways and associated with diseases like cancer and inflammatory conditions. In this study, we focused on the design and analysis of _N-aryl-benzimidazole_ derivatives as potential inhibitors of the HSP90 protein, which plays a crucial role in numerous signaling pathways related to cancer, inflammation, and other diseases [39]. Our approach combined pharmacodynamic modeling, molecular docking, and molecular dynamics simulations to explore the interactions between these compounds and HSP90, as well as their physicochemical and pharmacokinetic properties. The pharmacophore model developed from the MEY ligand successfully highlighted key features for effective binding in the HSP90 active site. These features included hydrogen bonding and hydrophobic interactions, which are well-documented in the literature as critical for HSP90 inhibition [40]. The selected compounds demonstrated compatibility with these critical binding characteristics, showing a similar interaction profile to the MEY ligand. Specifically, hydrophobic interactions with residues such as Met98 and Ala55 played an essential role in stabilizing the ligand-protein complex. This supports the notion that these compounds are capable of mimicking known interaction patterns, which is crucial for developing effective inhibitors [41]. The physicochemical properties of the top lead compounds were also favorable for drug development. Their molecular weights and volumes were within acceptable limits, ensuring good pharmacokinetics. The TPSA values indicated adequate membrane permeability, while the LogP values were generally optimal for effective distribution, aligning with the expected range for drug-like molecules. However, some compounds showed slightly lower solubility, which could affect bioavailability; this is consistent with findings from other studies that emphasize the importance of balancing solubility and lipophilicity \begin{table}
\begin{tabular}{c c c c} \hline \hline  & **HSP90\_L1** & **HSP90\_L2** & **HSP90\_MEY** \\ \hline \(\Delta\text{E}_{\text{VDW}}\) & \(-\)39.99 & \(-\)35.12 & \(-\)37.74 \\ \hline \(\Delta\text{E}_{\text{EEL}}\) & \(-\)53.49 & \(-\)41.46 & \(-\)40.74 \\ \hline \(\Delta\text{E}_{\text{PB}}\) & 63.30 & 48.18 & 51.44 \\ \hline \(\Delta\text{E}_{\text{NPOLAR}}\) & \(-\)4.14 & \(-\)3.81 & \(-\)3.93 \\ \hline \(\Delta\text{G}_{\text{GAS}}\) & \(-\)93.49 & \(-\)76.58 & \(-\)78.48 \\ \hline \(\Delta\text{G}_{\text{SOLV}}\) & 59.16 & 44.37 & 47.51 \\ \hline \(\Delta_{TOTAL}\) & \(-\)34.33 & \(-\)32.21 & \(-\)30.97 \\ \hline \hline \end{tabular}
\end{table} 
Table 5: Binding free energy, reported in kcal.mol\({}^{-1}\) for each system, was computed using MM-PBSA techniques. for drug efficacy [42]. Nevertheless, the overall drug-likeness scores derived from ADMET predictions confirmed that these compounds hold promise for further optimization. Our molecular dynamics simulations revealed that compound L1 exhibited exceptional stability in its complex with HSP90, with an average RMSD of 0.1219 nm, much lower than the reference drug MEY (0.413 nm). This indicates that L1 formed a highly stable complex with the HSP90 protein, which is a critical factor for the selective inhibition of its function. On the other hand, compound L2 showed a slightly less stable interaction but still demonstrated better stability than MEY. These findings align with previous studies, which also reported that lower RMSD values correlate with stronger and more stable ligand-protein binding [43]. Moreover, the RMSF and Rg analyses confirmed that the structural integrity of HSP90 was well-maintained during the simulations, even in the presence of the proposed inhibitors. The consistent SASA profiles further supported the notion that L1 and L2 interact stably with the protein's active site, facilitating efficient binding throughout the simulation period.