Unveiling the Anticancer Potential: Computational Exploration of Nitrogenated Derivatives of (+)-Pancratistatin as Topoisomerase I Inhibitors

Cancer poses a substantial global health challenge, driving the need for innovative therapeutic solutions that offer improved effectiveness and fewer side effects. Topoisomerase I (Topo I)
has emerged as a validated molecular target in the pursuit of developing anticancer drugs due to
its critical role in DNA replication and transcription. (+)-Pancratistatin (PST), a naturally occurring
compound found in various Amaryllidaceae plants, exhibits promising anticancer properties by inhibiting Topo I activity. However, its clinical utility is hindered by issues related to limited chemical
availability and aqueous solubility. To address these challenges, molecular modelling techniques,
including virtual screening, molecular docking, molecular mechanics with generalised born and
surface area solvation (MM-GBSA) calculations, and molecular dynamics simulations were utilised to
evaluate the binding interactions and energetics of PST analogues with Topo I, comparing them with
the well-known Topo I inhibitor, Camptothecin. Among the compounds screened for this study, nitrogenated analogues emerged as the most encouraging drug candidates, exhibiting improved binding
affinities, favourable interactions with the active site of Topo I, and stability of the protein-ligand
complex. Structural analysis pinpointed key molecular determinants responsible for the heightened
potency of nitrogenated analogues, shedding light on essential structural modifications for increased
activity. Moreover, in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET)
predictions highlighted favourable drug-like properties and reduced toxicity profiles for the most
prominent nitrogenated analogues, further supporting their potential as effective anticancer agents.
In summary, this screening study underscores the significance of nitrogenation in augmenting the anticancer efficacy of PST analogues targeting Topo I. The identified lead compounds exhibit significant
potential for subsequent experimental validation and optimisation, thus facilitating the development
of novel and efficacious anticancer therapeutics with enhanced pharmacological profiles.