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Inhibitor Designing Based on Amino Acids and Nucleobases for Bruton’s Tyrosine Kinase (BTK) by Computational Methods

Behzadi, Ali Asghar | 2024

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  1. Type of Document: M.Sc. Thesis
  2. Language: Farsi
  3. Document No: 57136 (03)
  4. University: Sharif University of Technology
  5. Department: Chemistry
  6. Advisor(s): Fattahi, Alireza
  7. Abstract:
  8. The enzyme Bruton's tyrosine kinase (BTK) is one of the essential proteins that plays a vital role in the proliferation of B lymphocyte cells. Therefore, it is considered a primary target for restricting the growth of corresponding cancer cells. The side effects of BTK inhibitors, as commonly available drugs, have always been a considerable concern, and efforts to find a more effective drug with fewer side effects have never been rare. Among them, drugs with selectively chosen structures from nature are promising to improve these side effects and achieve greater acceptance through the body's natural system. To address this, innovative drug design methods were employed using various tools, all derived from the power of computation. To ensure results, the drug Nemtabrutinib, previously subjected to laboratory testing, was chosen as a benchmark for designing a novel drug. The combination of amino acids and nucleotide bases represents our goal in designing a new Bruton's tyrosine kinase inhibitor. To achieve this, using the Spartan software, Nemtabrutinib, underwent initial evaluation, and 116 different possible structures were designed using cytosine, adenine, and guanine combined with natural amino acids that could reflect surface features, volume, electrostatic potential map, and to some extent, spatial conformation. After screening based on the mentioned features, 22 structures remained. These structures were further examined for their interaction with the target enzyme using AutoDock Vina software and compared with the interaction reported by precise laboratory methods for Nematibrutinib. Considering the binding affinity to the active site, five structures were selected. The remaining structures were optimized using Gaussian software with higher computational power and were thoroughly examined for interaction on the protein surface with high performance blind docking. Among remaining five structures, three of them exhibited satisfactory performance compared to Nemtabrutinib based on blind search docking outcome; they were prepared for molecular dynamics simulation to investigate binding free energy and the behavior of protein and ligand in complex with higher accuracy. Finally, with careful analysis, the structure S11 composed of phenylalanine, glycine, proline, and cytosine was introduced as a suitable alternative with natural components for Nemtabrutinib
  9. Keywords:
  10. Anticancer Drugs ; Inhibitor ; Molecular Dynamic Simulation ; Computational Method ; Bruton’s Tyrosine Kinase

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