Computational study of Fostemsavir reactivity to understand its degradation properties and its intrinsic stability through DFT and MD approach

Although several drugs are available for the treatment of HIV infections, it remains a threat to the global population. Fostemsavir is an anti-retroviral drug approved currently for the treatment of HIV patients. It's the first drug in the class of HIV attachment inhibitors. It’s a prodrug of Temsavir. The intrinsic stability data of Fostemsavir under stress environments, like oxidative and hydrolytic conditions, will help understand the formation of any degradation products. The knowledge of stability may be useful in the development of other formulations and for identifying the degradation products. Here, computational studies have been carried out using the Density functional theory (DFT) to understand the local reactivity of the molecule and to predict the oxidative degradation products bond dissociation energy (BDE) is calculated. The prone sites for hydrolytic attacks are studied using molecular dynamics simulations. • DFT analysis elucidated the electronic structure and intrinsic stability of fostemsavir. • HOMO–LUMO and electron density maps identified key reactive degradation sites. • BDE calculations revealed the most labile bonds driving degradation pathways. • MD and RDF analyses clarified hydrolysis mechanisms at the molecular level. • Integrated DFT–MD approach explains fostemsavir reactivity and stability behavior.