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طراحی بازدارنده نوین پروتئین شوک حرارتی 90 (HSP90) بر اساس مولکول های زیستی طبیعی با استفاده از روش های محاسباتی
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طراحی بازدارنده نوین پروتئین شوک حرارتی 90 (HSP90) بر اساس مولکول های زیستی طبیعی با استفاده از روش های محاسباتی

باوفا طرقبه، علیرضا Bavafa Torghabeh, Alireza

Computational Design of a Novel Inhibitor based on Natural Biomolecules for Heat Shock Protein 90 (HSP90)

Bavafa Torghabeh, Alireza | 2025

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  1. Type of Document: M.Sc. Thesis
  2. Language: Farsi
  3. Document No: 58284 (03)
  4. University: Sharif University of Technology
  5. Department: Chemistry
  6. Advisor(s): Fattahi, Alireza
  7. Abstract:
  8. In this study, the primary focus was on designing a novel drug scaffold aimed at inhibiting the HSP90 enzyme—an enzyme that, unlike many others, is intrinsically active and does not require upstream regulators for its function. This characteristic has made HSP90 a crucial therapeutic target in the treatment of various cancers and certain viral diseases. Recent studies have shown that the overactivity of this enzyme contributes to signaling pathways involved in cell proliferation, survival, and migration, and that its inhibition can arrest the growth of cancer cells.
    To develop an effective compound for the specific inhibition of HSP90’s active site, a thorough examination of pharmacological parameters—particularly pharmacokinetics and pharmacodynamics—was essential. Amino acids and nucleobases were incorporated into the molecular structure to improve biological properties and enable targeted drug delivery; by exploiting cellular transporters, these moieties increased stability and reduced systemic distribution. Given the practical and economic limitations of extensive experimental assays, computational methods were employed to assess pharmacodynamic features. This approach not only reduced cost and time but also allowed for more precise, targeted screening. Geldanamycin was chosen as the reference ATP-site inhibitor of HSP90 for validation. The binding behavior of geldanamycin was analyzed using Gaussian for quantum-mechanical calculations, AutoDock for molecular docking, and GROMACS for molecular dynamics simulations. Among 328 designed molecules, ligand 146 emerged as the top candidate based on binding energy, dynamic indices (RMSD, Rg, RMSF), enzyme–ligand distance, and binding free energy. Analysis revealed that ligand 146 closely resembles geldanamycin both structurally and functionally, outperforming it on certain metrics. Consequently, ligand 146 stands out as a promising candidate for further development as an HSP90 inhibitor.
  9. Keywords:
  10. Drug Design ; Molecular Docking ; GROMACS Software ; Cancer ; Natural Compounds ; Advanced Computational Chemistry Methods ; AutoDock Software

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