Potentilla nepalensis, a member of the Rosaceae family, exhibits a wide range of medicinal properties as an effective herbal remedy. Previous investigations have characterized forty phytochemical compounds (PCs) isolated from root and stem fractions using n-hexane (NR and NS) as well as methanolic (MR and MS) solvents. Nonetheless, the specific influence of these PCs on human genetic elements and their physiological functions remain unexplored until now. This research utilized approaches including network pharmacology, molecular docking, molecular dynamics simulations (MDSs), and MMGBSA techniques. SMILES structures of the PCs retrieved from PubChem served as inputs for DIGEP-Pred, resulting in the detection of 764 target genes. Enrichment analyses of these genes provided insights into their ontological classifications, associated biological pathways, linked disorders, and relevant pharmaceuticals. Protein-protein interaction (PPI) networks generated via String DB, along with topological analysis conducted in Cytoscape version 3.10, highlighted three key targets: TP53 associated with genes induced by MS, NR, and NS extracts; and HSPCB as well as Nf-kB1 linked to MR-induced genes. Among the 40 PCs evaluated, compounds 1b (from MR) and 2a (from MS) displayed superior docking energies (kcal/mol) against the p53 protein at −8.6 and −8.0, respectively, whereas compounds 3a (NR), 4a, and 4c (NS) showed strong affinities with the HSP protein at −9.6, −8.7, and −8.2. Analyses through MDS and MMGBSA confirmed the stability of these ligand-protein complexes, characterized by minimal structural fluctuations and favorable binding free energies. The targets uncovered in this work play significant roles in various malignancies. Therefore, additional experimental validation via in vitro and in vivo assays is recommended to elucidate the precise molecular actions and underlying mechanisms of these targets across multiple cancer models, incorporating the PCs derived from P. nepalensis.
