Loading...

Investigating the Effect of the Proposed CSF-1R Protein Inhibitor,with a Structure Containing Natural Biomolecules and based on the Approved Drug Vimseltinib

Ebtehaj, Pouria | 2023

41 Viewed
  1. Type of Document: M.Sc. Thesis
  2. Language: Farsi
  3. Document No: 56525 (03)
  4. University: Sharif University of Technology
  5. Department: Chemistry
  6. Advisor(s): Fattahi, Alireza
  7. Abstract:
  8. Vimseltinib, a small molecule inhibitor, represents a promising avenue for combating cancers linked to macrophage-associated processes through its targeted action on the CSF1R tyrosine kinase receptor. CSF1R, a pivotal member of the tyrosine kinase receptor family, plays a crucial role in macrophage differentiation and function. This protein's significance is underscored in conditions such as tenosynovial giant cell tumors (TGCTs) and the presence of tumor-associated macrophages, wherein overproduction of CSF1 by neoplastic cells recruits CSF1R-dependent immune cells, fostering tumor expansion. The intricate interplay extends to tumor-associated macrophages, particularly the M2 subtype, known for its anti-inflammatory properties. These macrophages, through cytokine release, compromise the immune response, contributing to cancer progression. CSF1 inducer, a cytokine secreted by various cells, including macrophages, binds to the CSF1R receptor, highlighting its relevance in various cancer types. While early targeted therapies like Pexidartinib have received approval for TGCT, they exhibit off-target effects that limit their efficacy. Enter Vimseltinib, the next generation of selective CSF1R protein inhibitors, albeit still susceptible to off-target activity. In this context, our research endeavors to pioneer a nucleopeptide-based inhibitor design employing natural biomolecules. This innovative approach aims to minimize side effects, enhance permeability, ensure stability, and alleviate dose limitations associated with CSF1R tyrosine kinase inhibition. In this project, we embarked on a comprehensive search, evaluating 6,200 nucleopeptides to identify potential CSF1R protein inhibitors. Employing a multi-step approach, we harnessed computational methods to meticulously assess these nucleopeptides. Initially, utilizing Marvin software, we meticulously designed all 6,200 nucleopeptides. Subsequently, conformational distribution analysis was carried out using OpenBabel software, culminating in the determination of optimal three-dimensional structures for each molecule. For precise evaluation, we conducted multiple binding affinity calculations within the active site and the entire protein, leveraging AutoDock Vina software with optimized settings for maximum computational power. Subsequently, focusing on binding energy (Affinity), we identified 146 nucleopeptides with the most negative binding energies for the next phase. In this subsequent phase, we delved into further research, considering factors such as interacting amino acids, surface-to-volume ratio, polarizability, polar surface area (PSA), and ovality in the context of these nucleopeptides compared to the reference drug. Ten selected nucleopeptides were then subjected to molecular dynamics simulations and related analyses.Ultimately, through comprehensive evaluations, we have identified nine nucleopeptides exhibiting specific targeting capabilities, positioning them as potential alternatives to Vimseltinib. These nine nucleopeptides, listed in descending order of promise, are as follows: N3S, N6S, N4S, N2S, N1S, N5S, N7M, N9S, and N10S
  9. Keywords:
  10. Cancer ; Drug Design ; Targeted Druy Delivery ; Inhibitor ; Computational Method ; CSF1R Protein ; Nucleopeptides ; Targeted Therapy

 Digital Object List

 Bookmark

No TOC