Related Experiment Video
Updated: Aug 9, 2025
Examining BCL-2 Family Function with Large Unilamellar Vesicles
Published on: October 5, 2012
Reinstating apoptosis using putative Bcl-xL natural product inhibitors: Molecular docking and ADMETox profiling
Ibrahim Damilare Boyenle1,2, Abdeen Tunde Ogunlana2, Abdul-Quddus Kehinde Oyedele2,3
1Department of Nursing Science, College of Health Science, Crescent University, Abeokuta, Nigeria.
Objectives:
While a fine balance in the pro-apoptotic and anti-apoptotic family members of the B-cell lymphoma-2 (Bcl-2) protein family represents a normal signaling profile, a tilt in balance towards anti-apoptotic family members has fortified different forms of cancers with survival advantage and resistance against treatment. Induction of apoptosis is a key therapeutic approach in cancer drug discovery, and the inhibition of the anti-apoptotic B cell lymphoma extra-large (Bcl-xL) is a long-standing clinical target for cancer therapy. In this study, we combined computer-aided approaches to report putative binders for this target.
Methods:
Before our virtual screening campaign, we conducted a redocking experiment strategy of the x-ray bound inhibitor of the Bcl-xL protein with some of the available docking software at our disposal to determine the software with the best efficiency for this screening. iGEMDOCK emerged to reproduce the x-ray crystallographic information and was used to dock the library of ligand, which was developed from diverse literature reporting compounds with anti-apoptotic profiles through the Bcl-2 family.
Results:
Of the compounds in the library, alpha-mangostin and oubain scored as hits with binding energy values of -123.025 kcal/mol and -122.271 kcal/mol, respectively, which is more than -120.8 kcal/mol observed by the standard.
Conclusions:
These compounds revealed a more binding affinity potential than ABT-737, which is a standard inhibitor of the protein. In addition, these scaffolds not only interact with relevant and hotspot residues for the inhibition of Bcl-xL but also possess good pharmacokinetic and excellent toxicity, an endpoint that should be considered for further testing and drug development.
Insights
Computer-aided drug discovery identified alpha-mangostin and oubain as potent inhibitors of B-cell lymphoma-extra-large (Bcl-xL), a key target in cancer therapy. These compounds show promise for developing new anti-cancer drugs by inducing apoptosis.
Area of Science:
- Biochemistry
- Computational Chemistry
- Pharmacology
Background:
- Dysregulation of the B-cell lymphoma-2 (Bcl-2) protein family, particularly an increase in anti-apoptotic members, contributes to cancer cell survival and treatment resistance.
- Inhibiting the anti-apoptotic protein B-cell lymphoma extra-large (Bcl-xL) is a critical therapeutic strategy in oncology.
- Targeting Bcl-xL aims to restore apoptosis, a programmed cell death pathway, in cancer cells.
Purpose of the Study:
- To identify novel small molecules that inhibit the anti-apoptotic protein Bcl-xL using computational approaches.
- To explore computer-aided drug design strategies for discovering potential anti-cancer therapeutics targeting Bcl-xL.
- To report putative binders for Bcl-xL based on virtual screening.
Main Methods:
- A redocking strategy was employed to validate docking software efficiency using a known Bcl-xL inhibitor.
- iGEMDOCK software was selected for virtual screening based on its ability to reproduce crystallographic data.
- A library of compounds with reported anti-apoptotic profiles was docked against the Bcl-xL target.
Main Results:
- Alpha-mangostin and oubain were identified as top-scoring compounds with binding energies exceeding the standard inhibitor (-123.025 kcal/mol and -122.271 kcal/mol, respectively).
- These identified compounds demonstrated superior binding affinity compared to the standard inhibitor ABT-737.
- The identified scaffolds interact with key residues essential for Bcl-xL inhibition.
Conclusions:
- Alpha-mangostin and oubain exhibit significant potential as Bcl-xL inhibitors, surpassing the efficacy of the current standard.
- These compounds possess favorable pharmacokinetic properties and low toxicity profiles, making them suitable candidates for further drug development.
- The study highlights the utility of computational methods in identifying promising anti-cancer drug leads targeting Bcl-xL.
More Related Videos
08:49Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
19:44Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
Published on: May 30, 2012
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
01:17The Extrinsic Apoptotic Pathway