Targeting Anti-Apoptotic Bcl-2 Proteins with Triterpene-Heterocyclic Derivatives: A Combined Dual Docking and...

Area of Science:

• Biochemistry and Molecular Biology
• Medicinal Chemistry
• Computational Drug Discovery

Background:

• Anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl-xL, Mcl-1) are frequently overexpressed in various cancers.
• This overexpression contributes to tumor progression and resistance to cancer therapies, making these proteins attractive therapeutic targets.

Purpose of the Study:

• To identify novel betulin derivatives as potential inhibitors of Bcl-2, Bcl-xL, and Mcl-1.
• To evaluate the binding stability and energetics of promising inhibitor candidates using computational methods.

Main Methods:

• Virtual screening of a betulin derivative library against Bcl-2 family proteins using molecular docking (AutoDock Vina, Glide).
• Shortlisting top-ranked compounds based on consensus scoring from two docking engines.
• Assessing binding stability of selected compounds via 100 ns molecular dynamics (MD) simulations.
• Calculating binding free energies (ΔG_bind) using Prime MM-GBSA.

Main Results:

• Dual docking and MD simulations identified BOxNaf1 and BT3 as stable binders to all three target proteins.
• Further analysis integrating MM-GBSA and MD stability data highlighted BOxNaf1 and BOxPhCl1 as the most promising multi-target candidates.
• BT3 demonstrated MD stability but weaker MM-GBSA energetics, positioning it as a backup candidate.

Conclusions:

• Betulin derivatives, particularly BOxNaf1 and BOxPhCl1, show significant potential as novel multi-targeting anticancer agents against the Bcl-2 family.
• Computational approaches combining docking, molecular dynamics, and binding energy calculations are effective for identifying lead compounds for cancer therapy.