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Design a New Sugar- amino Acid-based Drug Structure as an Alternative to Methotrexate, with the Aim of Treating Leukemia and some Autoimmune Diseases

Shapouri, Amin Mohammad | 2022

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  1. Type of Document: M.Sc. Thesis
  2. Language: Farsi
  3. Document No: 54865 (03)
  4. University: Sharif University of Technology
  5. Department: Chemistry
  6. Advisor(s): Fattahi, Alireza
  7. Abstract:
  8. This project aims to design a drug to fight leukemia and some autoimmune diseases having few side effects. These drugs are composed of natural sugar and amino acid structures. Among the various treatments available, drug structures as inhibitors of enzymes involved in cancer-related cellular processes is an important treatment. Methotrexate is one of the most widely used anticancer drugs in the last half-century and treats leukemia and many autoimmune diseases such as psoriasis. It is a derivative of folic acid (vitamin B9) and one of the drugs with specific properties. It is an anti-folate whose anti-metabolic effects can help kill cancer cells. One of the problems with using this drug to treat cancer is its many side effects. For this reason, designing drugs with the efficacy of methotrexate and having fewer side effects is of great importance for the treatment of this disease. In this study, according to the structure of the current drug and the relevant enzyme and considering characteristics such as volume and electron density distribution, we designed new drug structures that contain the natural skeleton of amino acids and sugars. These structures were designed using computational methods such as molecular dynamics, Quantum mechanics, and molecular docking methods with the help of Gromacs, Gaussian, Autodock, etc., software programs. The results of this study suggested a suitable alternative to methotrexate for the treatment of leukemia, psoriasis, and refractory cancers, with fewer side effects due to the use of natural structures and better performance due to stronger interaction with the target enzyme. According to the results of Gromacs calculations, the binding free energy of the designed ligand was about twice less than the original drug, indicating that it had a stronger interaction with the target enzyme. Also, mutations in residues like Alanine-31 and glutamine-35 may be produced by cancer cells in the structure of this protein and disrupt the function of the drug. Designed drugs showed better performance and resistance to these mutations. The name of the designed ligand is ((R)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-(4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)phenyl)propanoyl)-D-glutamic acid.

  9. Keywords:
  10. Inhibitor ; Drug Design ; Computational Design ; Cancer Treatment ; Anticancer Drugs ; Leukemia ; Amino Acid ; Sugars ; Methotrexate ; Autoimmune Diseases

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