Loading...

Design and Computational Evaluation of Sugar-Amino Acid Conjugates as CK2α Inhibitor

Nonanal Nahr, Milad | 2023

57 Viewed
  1. Type of Document: M.Sc. Thesis
  2. Language: Farsi
  3. Document No: 56067 (03)
  4. University: Sharif University of Technology
  5. Department: Chemistry
  6. Advisor(s): Fattahi, Alireza
  7. Abstract:
  8. The aim of this study is to devise innovative compounds that impede the function of CK2α enzyme by incorporating amino acids and sugars into their molecular structure. CK2α, a catalytic subunit of CK2 enzyme, operates autonomously and is the only continuously active kinase that does not require an upstream regulator. Emerging evidence highlights CK2α's crucial role in various cancers and infectious diseases, including Covid-19, indicating that suppressing its function could provide a promising approach to improve patient outcomes. To accomplish this objective, the drug design process must take into account both pharmacokinetic and pharmacodynamic properties. Pharmacokinetics, encompassing drug absorption, distribution, metabolism, and excretion (ADME), is the study of how drugs behave in the body. Previous studies have shown that integrating amino acids and carbohydrates into existing drug structures can enhance their ADME properties and can be used to exploit amino acid and carbohydrate transporters, thereby reducing adverse side effects. Thus, incorporating amino acids and glucose as building blocks in designing CK2α inhibitors was considered. To assess the pharmacodynamic properties of the newly designed drug structure, computational methods were employed. Silmitasertib, as a reference drug that targets the ATP site of CK2α enzyme and has been experimentally shown to have excellent pharmacodynamic properties, was employed for comparative analysis with the designed molecules using quantum mechanics, molecular docking, and molecular dynamics simulations. During the analysis, various factors, including the degree of volume similarity to Silmitasertib and their binding energy to the target site, were considered. The results showed that molecule a02 had a high degree of similarity to Silmitasertib in terms of binding to CK2α. A range of analyses, such as RMSD, Rg, RMSF, SASA, the number of contacts, the number of hydrogen bonds, and the binding free energy, were conducted to further support this discovery. Based on the findings, molecule a02 emerged as the most promising candidate for a CK2α inhibitor drug. In conclusion, this research provides valuable insights into drug design that considers both pharmacokinetic and pharmacodynamic properties. The incorporation of amino acids and glucose as building blocks improves the pharmacokinetic properties of drugs, and computational methods assist in determining the pharmacodynamic properties of drugs. The encouraging computational findings of the a02 molecule as a CK2α inhibitor indicate that this compound holds significant potential for research and development in the field of drug design
  9. Keywords:
  10. Computational Fluid Dynamics (CFD) ; Amino Acid ; Glucose ; Drug Design ; GROMACS Software ; Kinase Protein ; Enzymatic Inhibition

 Digital Object List

 Bookmark

No TOC