Multidrug resistance (MDR) poses a challenge in contemporary pharmacotherapy, significantly reducing the efficacy of chemotherapeutic agents. Among the array of mechanisms underpinning MDR, the upregulation of P-glycoprotein (P-gp), also known as MDR1 and encoded by the ABCB1 gene, emerges as an impediment in cancer treatment success. Plants from the Plectranthus genus (Lamiaceae) are recognised in traditional medicine for their diverse therapeutic applications. 7α-acetoxy-6β-hydroxyroyleanone (Roy), the principal diterpene derived from Plectranthus grandidentatus Gürke, has exhibited anti-cancer properties against various cancer cell lines. Previously synthesized ester derivatives of Roy have shown enhanced binding affinity with P-gp. This study utilises previously obtained in vitro data on P-gp activity of Roy derivatives to construct a ligand-based pharmacophore model elucidating critical features essential for P-gp modulation. Leveraging this data, we predict the potential of five novel ester derivatives of Roy to modulate P-gp in vitro against resistant NCI-H460 cells. A set of 16 previously synthesized royleanone derivatives underwent in silico structure-activity relationship (SAR) studies. A binary classification model, differentiating inactive and active compounds, generated 11,016 Molecular Interaction Field (MIF) descriptors from structures optimized at the DFT theory level. Following variable reduction and selection, a subset of 12 descriptors was identified, yielding a model with two latent variables (LV), utilizing only 34.14 % of the encoded information for calibration (LV1: 26.82 %; LV2: 7.32 %). Ultimately, prediction of the activity of new derivatives suggested all have a high likelihood of activity, which will be validated through future in vitro biological assays.