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Design of Novel Drugs Based on Tyrosine and Phenylalanine Amino Acids to Inhibit Cyclin-Dependent Kinases 2 (CDK2) Proteins Modeled on Flavopiridol Drug

Aghili, Farshad | 2022

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  1. Type of Document: M.Sc. Thesis
  2. Language: Farsi
  3. Document No: 56104 (03)
  4. University: Sharif University of Technology
  5. Department: Chemistry
  6. Advisor(s): Fattahi, Alireza
  7. Abstract:
  8. Cyclin-dependent kinases 2 (CDK2) are one of the important proteins in cell cycle regulation and progression. In many human cancer cells, the activity of CDK2 kinases and their related subunits are deregulated, leading to tumor formation. Therefore, inhibition of this enzyme as an attractive therapeutic target can cause cancer cell death in glioblastoma and diffuse large B-cell lymphoma. Using new pharmaceutical structures based on sugar and amino acids is a new approach due to its greater efficacy and fewer side effects than old drugs. In this research, according to the structure of Flavopiridol as one of the CDK2 inhibitors, the active site of CDK2, and the structure of ATP molecule, 50 drug structures were designed. At first, basic optimizations were done by Spartan software, and 34 structures were screened based on area, volume, and electrostatic potential map features. Next, by using Autodock vina method, the binding affinity of structures to the active site of CDK2 enzyme was checked and after that, 4 structures were entered into the Gaussian program to perform more accurate optimizations. Then, Autodock methods were applied for all 4 structures along with the main drug and protein around the entire parts of protein to select the best structures for molecular dynamic simulation calculations and to calculate the binding free energy of these structures along with the main drug and protein with high accuracy. Finally, Glucose-Triazole-Tyrosin (YTG) and Glucose-Tyrosin-Proline (PYG) structures were introduced as inhibitors of the ATP binding site in CDK2 protein which are suitable structures for the Flavopiridol
  9. Keywords:
  10. Cancer ; Organic Inhibitors ; Molecular Docking ; Molecular Dynamic Simulation ; Flavopiridol Drug ; Cyclin-Dependent Kinases 2 (CDK2) ; Tyrosine ; Phenylalanine

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