66P - Targeting allosteric sites on PDK-1 and PLK-1 with bioactive compounds from <italic>Daucus carota</italic> as a potential therapy for triple-negative breast cancer

Background

Triple-negative breast cancer (TNBC) is a devastating subtype of breast cancer that lacks expression of estrogen receptors, progesterone receptors, and HER2. Targeting TNBC has been challenging due to the lack of specific therapeutic targets. However, recent studies have identified allosteric sites on the enzymes PDK-1 and PLK-1 as potential drug targets for TNBC. New medications for TNBC have considerable adverse effects, highlighting the need for more targeted and effective therapy.

Methods

In this study, we used computer-aided drug design (CADD) and theoretical chemistry techniques, including molecular docking, MM-GBSA calculation, molecular dynamic (MD) simulation, and a pharmacokinetic study, to identify bioactive compounds from Daucus carota that could bind to these allosteric sites and inhibit the activity of PDK-1 and PLK-1. DFT calculations confirmed the binding affinity and stability of the molecules. Machine-learning predictive models(QSAR) were used to find potential compounds against the two targets.

Results

Ten (10) lead compounds from Daucus carota's bioactive compounds are discovered; eight have more potential as PDK-1 and PLK-1 inhibitors than docetaxel and doxorubicin. Astragalin and Scolimoside showed substantial binding affinity and persistent interaction in the allosteric region of the two proteins. These compounds are stable and fluctuate little after 50ns of MD simulation. DFT analysis confirms enhanced bioactivity and chemical reactivity of hit compounds with favourable intramolecular charge transfer between electron-donor and electron-acceptor groups. The predicted QSAR model showed the efficiency of certain compounds as PDK-1 and PLK-1 inhibitors (pIC50).

Conclusions

This study provides evidence that targeting PDK-1 and PLK-1 with bioactive compounds from Daucus carota may be an effective method for the treatment of TNBC.

Clinical trial identification

Editorial acknowledgement

Associate Professor Muhammad Muddassar COMSATS University Islamabad.

Legal entity responsible for the study

K.Y. Raheem.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.