Comparative study on the inhibitory potential of anticancer drugs and natural compounds against PHB proteins

Prohibitin 1 (PHB1) and Prohibitin 2 (PHB2) play a crucial role in tumorigenesis and are emerging targets for anticancer therapy. This study applied a structure-based drug repurposing approach, screening 35 chemotherapeutic and natural compounds against PHB1 and PHB2 through molecular docking. Six top candidates Ibrutinib, Daunorubicin, Doxorubicin, Rutin, Flavopiridol, and Camptothecin exhibited binding affinities ranging from -9.7 to -10.5 kcal/mol. ADMET profiling identified Ibrutinib and Flavopiridol as drug-like with favourable pharmacokinetics, whereas Rutin violated Lipinski's rules. Molecular dynamics simulations over 200 ns revealed high stability of Ibrutinib-PHB complexes, supported by low RMSD values (∼1.3-2.2 Å). MM/PBSA free energy calculations confirmed Ibrutinib as the strongest binder (-92.1 and -71.6 kJ/mol for PHB1 and PHB2). These findings position Ibrutinib as a promising PHB-targeting agent for cancer therapy. Further <i>in vitro</i> and <i>in vivo</i> validations are essential to confirm its therapeutic potential.