Screening of the Prodiginine Molecules as BH3-Mimetics against the Developed Bcl-2 Antiapoptotic Chemotherapeutic Resistance: A Molecular Docking and ADMET Study Supported by Molecular Dynamics Simulations.

Background: Chemotherapy remains a primary treatment for stopping cancer cell growth. Unfortunately, resistance to chemotherapy is a challenge that leads to cancer relapse. Overexpression of the antiapoptotic proteins is a major cause of this resistance. BH3 mimetic compounds were developed in this work to deal with this issue by blocking the Bcl-2 antiapoptotic proteins. Currently, only a few BH3 mimetics are approved drugs, and even fewer can effectively target all antiapoptotic Bcl-2 proteins.

Objective: The present study aimed to explore and screen the prodiginine family of molecules for new potential and effective BH-3 mimetics.

Methods: Molecular docking and molecular dynamics (MD) simulations were used to assess the potential of 30 prodiginine analogs as BH3 mimetics, including the obatoclax molecule, a prodiginine member used in clinical trials as a BH3 mimetic.

Results: Molecular docking results showed four prodiginines to have lower free binding energy values for five Bcl-2 proteins (Bcl-2, Mcl-1, Bcl-w, Bcl-xl, and Bfl1) compared to the reference drug, obatoclax. The five analogs presented safe pharmacological profiles according to Lipinski's rule of five. Furthermore, MD simulations demonstrated butylcycloheptyl prodiginine- Bcl-2 and prodigiosin-R2-Bcl-xl complexes to be more stable than the reference complexes obatoclax-Bcl-2 and obatoclax-Bcl-xl.

Conclusion: Based on these results, butylcycloheptyl prodigiosin and prodigiosin-R2 could be more effective BH3 mimetics and should be further studied.