SYNERGIZING IN-SILICO APPROACHES OF NATURAL PRODUCT-BASED DRUG DISCOVERY AND DRUG REPURPOSING TO TARGET STATS IN GLIOB

Abstract

Background Glioblastoma, or Glioblastoma multiforme (GBM), is a primary central nervous system glioma that remains incurable due to the lack of effective treatments. This approach, encompassing both drug discovery and drug repurposing, presents a promising strategy against GBM. The JAK/STAT signaling cascade holds a pivotal role in various tumor-promoting functions and is implicated in the pathogenesis and progression of GBM. This study aims to inhibit this pathway by targeting STAT3 and STAT1 using an in-silico approach to identify potential inhibitors. The research focuses discovering the phytocompounds derived from various Indian medicinal plants known for their therapeutic applications and re-purposing FDA approved drugs directly derived from Drug Bank database. Phytochemicals from these plants were manually collected and curated based on their blood-brain barrier permeability using Swiss ADME. Molecular docking was conducted with PyRx, and docking scores were validated through CB-Dock2. Binding interactions were visualized with PyMOL and Discovery Studio. Additionally, ADMET analysis was performed using Swiss ADME and the PkCSM tool, while carcinogenicity and toxicity to cancer cell line was assessed with CarcinoPred-EL and CLC-Pred 2.0. Results Five phytocompounds, withametelin, isowithametelin, anolobine, withasomidienone and xylopine along with three FDA approved tirilazad, telmisartan and mizolastine were identified with some inhibitors showing promising pharmacological properties such as blood-brain barrier permeability, against STAT3. Most of these compounds also demonstrated strong binding affinity with STAT1 as well. Conclusion Some of the compounds derived from selected medicinal plants and few FDA approved drugs have the potential for being the potential drug candidates in the treatment of GBM. Their favorable docking scores indicate strong binding with targets and effective drug-like properties, qualify them as potential inhibitors of both STAT3 and STAT1.