Insight into the Structural and Dynamic Properties of Novel HSP90 Inhibitors through DFT Calculations and Molecular Dynamics Simulations

Context: Heat-shock proteins (HSPs), particularly HSP90, are critical molecular chaperones that maintain protein stability, especially in cancer cells. Elevated HSP90 levels in tumors aid in oncogenic protein stabilization. This study focuses on developing potent, selective HSP90 inhibitors to disrupt its chaperone function, targeting cancer cell survival. Using a de novo hybridization approach, we designed novel inhibitors by integrating structural fragments from a known HSP90-binding drug, leading to the creation of hybrid compounds C1, C2, and C3. A 300 ns molecular dynamics simulation of each system revealed that C1, C2, and C3 formed more stable complexes with HSP90 compared to the reference compound, MEY. RMSD, RMSF, Rg, SASA, and MM-PBSA metrics supported these findings. DCCM and FEL analyses confirmed that the inhibitors did not alter HSP90's initial configuration. Further DFT calculations with the B3LYP/6-311++(d,p) basis set assessed frontier molecular orbitals, MEP surfaces, ELF, LOL maps, TDOS and PDOS, affirming their potential as new anti-cancer therapies. Methods Maestro 11.8, Discovery Studio Visualizer, Gromacs-2023, Gaussian 16, and online platforms like SwissADME and ProTox-II were utilized. Fragments generated from eight known HSP90-binding drugs were subjected to SP-docking, leading to 170 fragments. The highest-scoring fragments were merged using the breed panel to create new HSP90 inhibitors. XP-docking and ADMET analyses identified C1, C2, and C3 as the most promising candidates. These compounds were selected for a 300 ns dynamic simulation and subsequent DFT calculations.