Skrining Virtual Senyawa Metabolit Sekunder Plantago major L. sebagai Inhibitor Protein NLRP3 untuk Penyembuhan Luka Diabetes

ROZIN DWI SALIM, Dr.apt. Rohmad Yudi Utomo, M.Sc.; Prof. Dr.rer.nat. apt. Triana Hertiani,M.Si.

2024 | Skripsi | FARMASI

Luka diabetes merupakan komplikasi diabetes melitus dengan adanya aktivasi berlebihan protein NLRP3. Protein NLRP3 memicu pyroptosis dan pelepasan proinflammatory cytokines yang berlebihan pada kondisi luka diabetes. Selain itu, protein NLRP3 memiliki varian mutasi yang beragam. Oleh karenanya, pengembangan inhibitor protein NLRP3 menjadi langkah potensial pada pengobatan luka diabetes. Senyawa metabolit Plantago major L. seperti Aucubin, Catalpol, dan Acetoside secara empiris dan eksperimental memiliki bioaktivitas sebagai anti-inflamasi dan penyembuhan luka. Penelitian ini bertujuan untuk mengembangkan inhibitor protein NLRP3 dalam penyembuhan luka diabetes menggunakan senyawa metabolit sekunder Plantago major L..

Penelitian ini merupakan penelitian in-silico dengan metode molecular docking. Penelitian diawali dengan kurasi data senyawa uji pada database IMPPAT, CMAUP, dan KNApSAcK, serta kurasi data protein target pada database PDB. Molecular docking dilakukan melalui Molecular Operating Environment pada protein NLRP3 wild type, serta model protein NLRP3 termutasi D305N dan T350M yang dibuat melalui homology modelling.

Protokol Molecular Docking dalam penelitian ini dinyatakan valid melalui hasil re-docking. Hasil skrining virtual menunjukkan senyawa Purpureaside C, Majoroside F5, Plantamajoside, Acteoside, NPC41503, dan Rehmannioside D pada Plantago major L. memiliki potensi sebagai inhibitor protein NLRP3 berdasarkan nilai skor docking yang rendah dibandingkan native ligand CRID3, serta kemampuannya dalam berikatan pada sub domain NBD, HD2, trLRR, dan residu kunci pada motif walker A. Model protein NLRP3 termutasi D305N dan T350M dinyatakan valid melalui plot Ramachandran. Dibandingkan dengan CRID3, Senyawa Plantago major L. mampu mempertahankan perubahan nilai skor docking pada model protein NLRP3 termutasi D305N dan T350M yang berkorelasi terhadap sindrom autoinflamasi.

Diabetic wounds are a complication of diabetes mellitus due to excessive activation of the NLRP3 protein. The NLRP3 protein triggers pyroptosis and the excessive release of proinflammatory cytokines in diabetes. In addition, the NLRP3 protein has a variety of mutation variants. Therefore, the development of NLRP3 protein inhibitors is a potential step in the treatment of diabetic wounds. Plantago major L. metabolite compounds such as Aucubin, Catalpol, and Acetoside empirically and experimentally have bioactivity as anti-inflammatory and wound healing. This research aims to develop NLRP3 protein inhibitors for healing diabetic wounds using the secondary metabolite compounds of Plantago major L.

This research is in silico research using the molecular docking method. The research began with data curation of test compounds in the IMPPAT, CMAUP, and KNApSAcK databases, as well as curation of target protein data in the PDB database. Molecular docking was carried out using the Molecular Operating Environment on the wild-type NLRP3 protein, as well as the D305N and T350M mutated NLRP3 protein models created through homology modeling.

The molecular docking protocol in this study is validated through re-docking results. The virtual screening results show that the compounds Purpureaside, Majoroside F5, Plantamajoside, Acteoside, NPC41503, and Rehmannioside D in Plantago major L. have potential as NLRP3 protein inhibitors based on their low docking score compared to the native ligand CRID3, as well as their ability to bind to the NBD, HD2, trLRR subdomain, and key residues in the Walker A motif. The D305N and T350M mutated NLRP3 protein models were declared valid via Ramachandran plots. Compared with CRID3, the Plantago major L. compound was able to maintain changes in docking score values in the D305N and T350M mutated NLRP3 protein models, which correlated with autoinflammatory syndrome.

Kata Kunci : Luka diabetes, NLRP3 kompleks, Plantago major L., Skrining virtual