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Targeting the BH3 domain mediated protein-protein interaction of Bcl-xL through virtual screening
Prasenjit Mukherjee1, Prashant Desai, Yu-Dong Zhou
1Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
Abstract:
Apoptosis, or programmed cell death, forms an important part of the cellular regulation machinery. The Bcl-2 protein family, comprising of proapoptotic and antiapoptotic members, forms an important part of the cells internal apoptotic pathway. Overexpression of the antiapoptotic members of the family in a number of cancer cell lines renders them immune to apoptosis and the ability to survive under conditions of cellular stress. Inhibition of the antiapoptotic members of the Bcl-2 family are, therefore, an interesting target for the development of anticancer therapy. An innovative structure-based virtual screening strategy was developed to identify inhibitors of Bcl-xL, an antiapoptotic member of the Bcl-2 family. Various innovative filters, such as receptor-based pharmacophore, cascade docking approach, cross-docking, and composite scoring with docking pose based descriptors were designed through exhaustive validation studies and implemented in the screening funnel. The 1.8 million 'big-n-greasy' subset from ZINC was screened using the protocol, and 45 compounds were finally selected for biological evaluation against Bcl-xL. The evaluation led to the identification of one low-micromolar and two weaker inhibitors belonging to novel scaffolds. Further evaluation of structure-activity relationships around these scaffolds could help in the development of anticancer leads against Bcl-xL.
Insights
Researchers identified novel anticancer drug leads by targeting Bcl-xL, a protein promoting cancer cell survival. This structure-based virtual screening approach identified promising compounds for further development against cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Apoptosis is crucial for cellular regulation.
- The Bcl-2 protein family regulates apoptosis, with antiapoptotic members promoting cancer cell survival.
- Inhibiting antiapoptotic Bcl-2 proteins is a promising anticancer therapy strategy.
Purpose of the Study:
- To identify novel inhibitors of Bcl-xL, an antiapoptotic protein, using a structure-based virtual screening approach.
- To develop an effective screening protocol for identifying potential anticancer agents targeting Bcl-xL.
Main Methods:
- Developed and validated a structure-based virtual screening strategy incorporating pharmacophore filtering, cascade docking, cross-docking, and composite scoring.
- Screened the 'big-n-greasy' subset of the ZINC database (1.8 million compounds).
- Selected 45 compounds for biological evaluation against Bcl-xL.
Main Results:
- Identified one low-micromolar inhibitor and two weaker inhibitors of Bcl-xL.
- The identified inhibitors belong to novel chemical scaffolds.
- The screening protocol demonstrated effectiveness in identifying potential Bcl-xL inhibitors.
Conclusions:
- The developed virtual screening strategy is effective for identifying Bcl-xL inhibitors.
- Novel scaffolds targeting Bcl-xL were discovered, offering potential for anticancer drug development.
- Further structure-activity relationship studies are warranted to optimize these leads into viable anticancer therapies.
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