Aleksya Drobshoff, & Dr. Ahmed Awad
Pancreatic ductal adenocarcinoma (PDAC), is the most deadly pancreatic cancer because of
insufficient detection techniques. This results in delayed diagnosis and late cancer stages,
severely limiting treatment options. The current treatment for PDAC is a nucleoside analogue,
Gemcitabine, which faces several drug-resistant mechanisms that hinder its chemotherapeutic potential. We propose a nucleoside analogue with a polyethylene glycol amino (PEGA) modification. The PEGA group is also hypothesized to serve as a chelating agent for zinc and iron ions. Given the importance of iron for RNR activation and zinc homeostasis in cancer, this modification can improve the chemotherapeutic potential of the drug. We have done computational studies including molecular docking using the internal coordinate mechanics algorithm (ICM), SWISS Absorption, Distribution, Metabolism, and Excretion (SWISSADME), and prediction of activity spectra for substances (PASS), utilizing the Way2Drug online application; We have also begun synthesizing the intended compound. The edock scores, the root mean square deviation (RMSD), and the H-bonding formation were analyzed on ICM. The PEGA moiety indicated a strong binding affinity to a known substrate binding residue in the catalytic site, Asn211, a vital component of catalytic processes. The pharmacokinetics and toxicity were assessed through SWISSADME, which demonstrated excellent solubility scores of logS -0.37 and showed non-toxic interactions with CYP isoenzymes. Through PASS prediction, the biological activity of the compound showed high potential as an RNR inhibitor, with a probability of activity (Pa) to probability of inactivity (Pi) of 0.174 to 0.011. In conclusion, the proposed analogue demonstrated promising target inhibition potency for further investigation via in vivo and in vitro studies.