Electronic Theses and Dissertation

Skizofrenia merupakan gangguan psikosis kronis yang melibatkan mekanisme neuroinflamasi melalui aktivasi mikroglia dan peningkatan sitokin proinflamasi, namun terapi berbasis NSAIDs yang tersedia saat ini masih memiliki efek samping yang merugikan. Penelitian ini bertujuan untuk mengeksplorasi potensi senyawa aktif ekstrak etanol daun tanaman kratom (Mitragyna speciosa) terhadap jalur molekuler neuroinflamasi skizofrenia melalui pendekatan in silico. Data sekunder fitokimia diperoleh dari LC-HRMS, kemudian disaring menggunakan analisis ADMET. Target protein senyawa tanaman kratom diidentifikasi dengan menggunakan tiga basis data, sedangkan target protein skizofrenia diidentifikasi dengan menggunakan empat basis data molekuler, lalu keduanya dianalisis untuk mendapatkan target umum. Jaringan interaksi protein (network pharmacology) dibangun menggunakan STRING dan Cytoscape, dilengkapi analisis Gene Ontology (GO) dan KEGG. Senyawa terpilih selanjutnya diuji melalui molecular docking menggunakan PyRx dan divisualisasi dengan PyMOL, serta divalidasi melalui Molecular Dynamics Simulations (MDS) selama 50 ns menggunakan YASARA. Hasil menunjukkan 62 senyawa teridentifikasi dari data LC-HRMS dengan 921 common target antara tanaman kratom dan skizofrenia. Analisis GO dan KEGG menetapkan jalur TLR4–SRC–PI3K–NF-κB sebagai kaskade neuroinflamasi sentral dengan protein SRC sebagai regulator utama. Hasil analisis Molecular docking menunjukkan Mitragynine Pseudoindoxyl (MP) memiliki binding affinity terbaik (−8,7 kcal/mol), paling mendekati kontrol aripiprazol (−8,6 kcal/mol) dengan kemiripan residu asam amino 70%. MDS mengonfirmasi stabilitas kompleks protein SRC–MP yang konstan. Berdasarkan hasil penelitian, disimpulkan bahwa MP merupakan kandidat agen terapi alami skizofrenia paling prospektif yang layak dikembangkan melalui pengujian eksperimental lebih lanjut.

Kata kunci: In silico, Mitragynine Pseudoindoxyl, Mitragyna speciosa Neuroinflammation, Schizophrenia, Virtual screening

Schizophrenia is a chronic psychotic disorder involving neuroinflammatory mechanisms through microglia activation and increased proinflammatory cytokines, but currently available NSAID-based therapies still have adverse side effects. This study aims to explore the potential of active compounds from kratom (Mitragyna speciosa) leaf ethanol extract on the molecular pathways of schizophrenia neuroinflammation through an in silico approach. Secondary phytochemical data were obtained from LC-HRMS, then filtered using ADMET analysis. Protein targets of kratom compounds were identified using three databases, while protein targets for schizophrenia were identified using four molecular databases, then both were analyzed to obtain common targets. A protein interaction network (network pharmacology) was constructed using STRING and Cytoscape, complemented by Gene Ontology (GO) and KEGG analyses. Selected compounds were then tested through molecular docking using PyRx and visualized with PyMOL, and validated through Molecular Dynamics Simulations (MDS) for 50 ns using YASARA. The results showed 62 compounds identified from LC-HRMS data with 921 common targets between kratom and schizophrenia. GO and KEGG analyses established the TLR4–SRC–PI3K–NF-κB pathway as a central neuroinflammatory cascade with SRC protein as the main regulator. Molecular docking analysis results showed Mitragynine Pseudoindoxyl (MP) had the best binding affinity (−8.7 kcal/mol), closest to the control aripiprazole (−8.6 kcal/mol) with 70% amino acid residue similarity. MDS confirmed the constant stability of the SRC–MP protein complex. Based on the results of the study, it was concluded that MP is the most prospective candidate for natural therapeutic agents for schizophrenia worthy for further experimental development. Keywords: In silico, Mitragynine Pseudoindoxyl, Mitragyna speciosa Neuroinflammation, Schizophrenia, Virtual screening