02879nas a2200253 4500008004100000245010400041210007300145260001500218300000900233490000700242520210500249653001102354653002602365653001202391653002702403653001902430653002202449653002802471100001702499700001502516700003102531700002302562856004002585 2026 eng d00aLC–MS Profiling, In Silico Docking–MD and ADMET of Uncaria gambir Roxb. for p38 MAPK Inhibition0 aLC–MS Profiling In Silico Docking–MD and ADMET of Uncaria gambir cApril 2026 a8-170 v183 a

Introduction: p38 mitogen-activated protein kinase (MAPK) is a pivotal regulator of inflammatory and cancer pathways. This study investigates phytochemicals from Bajakah (Uncaria gambir Roxb.) bark as potential p38 MAPK inhibitors, integrating LC–MS profiling with computational drug discovery. Methods: Bajakah bark extract was profiled by liquid chromatography–high-resolution mass spectrometry (LC–HRMS) to identify major phytochemicals. Promising non-toxic candidates were selected via in silico toxicity prediction (ProTox-II) and ADME assessment (pkCSM). Molecular docking against p38 MAPK (PDB ID: 3QUE) was performed using AutoDock Vina, followed by 50 ns molecular dynamics simulations with GROMACS and MM/PBSA binding free energy calculations using gmx_MMPBSA. Results: LC–HRMS identified ten major phytochemicals; 8-methylnaphthalene-1,2-diol (Diol) and methyl cinnamate exhibited non-toxic profiles (LD₅₀ > 2,600 mg/kg; no CYP450 liabilities) with favorable ADME properties. Molecular docking revealed binding energies of −8.04 kcal/mol (Diol), −11.4 kcal/mol (Skepinone-L reference), and −6.4 kcal/mol (methyl cinnamate). Both Diol and Skepinone-L engaged conserved hydrophobic residues (VAL38 and LYS53), with Diol showing additional engagement at LEU104, and docking RMSD validation within 2.5 Å. Molecular dynamics confirmed stable Diol–p38 complex binding (RMSD ~0.30 nm), with balanced solvent accessibility, stable dynamic binding dominated by electrostatic interactions, and adaptive conformational sampling. MM/PBSA analysis revealed binding free energies of −21.9 kcal/mol (Diol) and −32.9 kcal/mol (Skepinone-L), with Diol's affinity driven by electrostatic interactions (−29.62 kcal/mol). Conclusions: 8-Methylnaphthalene-1,2-diol emerges as a promising natural p38 MAPK inhibitor candidate with favorable safety profiles and dynamic binding properties, warranting biochemical validation and structure–activity relationship optimization.

10a2-diol10a8-methylnaphthalene-110abajakah10acomputational modeling10aDrug discovery10aMolecular docking10aPhytochemical profiling1 aAmbeng, Yudi1 aKania, Nia1 aOktaviyanti, Ika, Kustiyah1 aRahman, Eka, Yudha uhttps://www.phcogj.com/article/2585