In-silico Elucidation of the Anti-Cancer Potential of Perillyl Alcohol Derivatives as Inhibitors of Human Farnesyl Pyrophosphate Synthase (PDB: 4AQ3)

Abstract

Farnesyl pyrophosphate synthase (FPPS) is a well-established enzyme in the mevalonate pathway, which helps activate small GTPases that play a role in cancer. Perillyl alcohol (POH), a natural compound known for its anticancer effects, has limitations in terms of its potency and pharmacokinetic properties. This study outlines several steps, including preparing the target, validating the docking protocol, and performing structure-based virtual screening on a library of 50 modified POH derivatives. It also includes post-docking interaction analysis, molecular dynamics simulations, binding energy calculations, and ADMET profiling. Some POH derivatives, like POH D3, D7, and D45, showed better docking scores than the original POH, stabilized important interactions with key residues (Lys256, Tyr204, and Phe113), and maintained stability during simulations, with stronger hydrogen bonding. These modified POH compounds are promising leads for FPPS inhibition, showing potential for further validation through enzyme and cell-based studies. This research combines validated computational techniques with early-stage development criteria to identify natural product-based chemotypes as potential non-bisphosphonate FPPS inhibitors.