In silico identification of alkaloids and repurposed drugs as potential small-molecule inhibitors of GOLPH3 in cancer using molecular docking, molecular dynamics, and MM-PBSA analysis

GOLPH3 is a PI(4)P-binding oncoprotein implicated in tumor progression, metastasis, and drug resistance, yet no direct small-molecule inhibitors of this target have been reported. In this study, we investigated the inhibitory potential of alkaloids and repurposable FDA-approved drugs against the GPP34 domain of GOLPH3 using molecular docking, molecular dynamics (MD) simulations, and MM-PBSA analysis. A total of 200 alkaloids and 10 representatives each from statins, anti-inflammatories, and antidepressants were screened. Docking results identified bisleuconothine A and notoamide D as the most promising alkaloids, each binding strongly to the PI(4)P-binding pocket (− 10.5 kcal/mol). Among FDA-approved drugs, pitavastatin showed the highest affinity (− 8.4 kcal/mol). MD simulations demonstrated that these compounds formed stable and energetically favorable complexes with GPP34, as validated by RMSD, RMSF, SASA, Rg, hydrogen-bonding, free energy landscape, and principal component analyses. MM-PBSA calculations further confirmed favorable binding free energies, with critical contributions from Phe80, Leu187, and the essential PI(4)P-binding residue Trp81. ADMET and oral bioavailability predictions indicated satisfactory pharmacokinetic profiles, particularly for the alkaloids. Collectively, this work provides the first computational evidence of alkaloid and statin scaffolds as potential GOLPH3 inhibitors, establishing a foundation for future in vitro and in vivo validation toward developing novel anti-GOLPH3 therapeutics.