STUDIES OF INHIBITION POTENTIAL OF TEOPHYILLINE DERIVATIVE COMPOUNDS AGAINST JAK3 AS ANTI-INFLAMMATORY AGENTS IN COVID-19 TREATMENTS

• Main Author: Mariam Anisa, Putri
• Format: Final Project
• Language: Indonesia
• Subjects: Kimia
• Online Access: https://digilib.itb.ac.id/gdl/view/75513
• Institution: Institut Teknologi Bandung

In early 2020, the world was hit by Coronavirus Disease 2019 (Covid-19) pandemic. The pandemic spread across nations rapidly and caused millions of casualties. Globally, as of 5 July 2023, there have been 767.726.861 confirmed cases of Covid-19, including 6.948.764 deaths, reported to World Health Organization (WHO). The highest mortality factor is acute respiratory distress syndrome caused by cytokine storm. Cytokines storm is hyperinflammation because of uncontrollable and excessive cytokines release. Janus Kinase inhibitors (JAKi) can be used as anti-inflammatory agents in immunomodulatory therapy for cytokines storm. Janus Kinase is a non-receptor tyrosine kinase type of enzyme that consist of 4 enzymes, JAK1, JAK2, JAK3, and TYK2. Tofacitinib (JAK1/JAK3 inhibitor) is one of the JAKis that were recommended by WHO. Even though it works well as an anti-inflammatory agent, it also has side effects such as diarrhea, nausea, vomiting, headache, abdominal pain, acne vulgaris, and hepatotoxicity. So, it is important to find the JAK3 inhibitor alternatives which have lesser side effects. Thus, this study focuses on finding tofacitinib alternatives as JAK3 inhibitor using molecular docking analysis. Theophylline derivates compounds were chosen because these compounds have active chromophores of JAK3. Interaction between 14 theophylline derivates with active site of JAK3 were analyzed using Autodock Vina. The docking procedures were conducted in 2 main steps, selecting and validating the docking parameter and then performing molecular docking simulations on selected control and tested compounds against JAK3. The results show that all tested compounds interact with catalytic residue (Leu905) and gatekeeper residue (Met902) of JAK3. The docking scores range between –6,9 kcal/mol up to –8,3 kcal/mol with binding similarity around 50 – 85,71% towards tofacitinib (as control). Compound 14 (N-{3-[(1,3-dimethyl-2,6-dioxo-2,3,6,7- tetrahydro-1H-purin-7-yl)methyl]phenyl}-2-(4-methylpiperazin-1-yl)acetamide) has the best interactions with JAK3 among all tested compounds. The docking score is –8,3 kcal/mol with 71,43% binding similarity towards tofacitinib. This compound has benzyl, amide, and piperazine groups in its structure. Overall, it was concluded that compound 14 has potential as JAK3 inhibitors. The inhibition of compound 14 against JAK3 can be further analyzed with molecular dynamics and lab tests.