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Published on: January 22, 2019
In-silico screening of new potential Bcl-2/Bcl-xl inhibitors as apoptosis modulators
Anna Maria Almerico1, Marco Tutone, Antonino Lauria
1Dipartimento Farmacochimico, Tossicologico e Biologico, Università degli Studi di Palermo, Via Archirafi 32, 90123, Palermo, Italy. almerico@unipa.it
Abstract:
One of the major problems in the fight against cancer is drug-resistance, which, at a molecular level, can be acquired through mutations able to deactivate apoptosis. In particular, proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-xl and Bcl-2, are overexpressed in many tumours. The development of new inhibitors of these proteins as potential anticancer therapeutics represents a new frontier. In this work, we carried out an in-silico screening of compounds from a free database of more than 2 million structures (ZINC database), which allowed us to identify 17 sulfonamide derivatives as new potential inhibitors; these are currently undergoing biological evaluation.
Insights
Drug resistance in cancer is a major challenge, often caused by mutations affecting apoptosis. Researchers screened over 2 million compounds, identifying 17 potential new drug inhibitors targeting Bcl-2 family proteins for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Drug resistance is a significant obstacle in cancer treatment, often linked to apoptosis regulation.
- Proteins of the Bcl-2 family, such as Bcl-xl and Bcl-2, are key regulators of programmed cell death and are frequently overexpressed in tumors.
- Targeting these anti-apoptotic proteins represents a promising strategy for developing novel anticancer therapeutics.
Purpose of the Study:
- To identify novel small molecules that inhibit the function of anti-apoptotic proteins within the Bcl-2 family.
- To explore the potential of sulfonamide derivatives as anticancer agents targeting drug resistance mechanisms.
Main Methods:
- An in-silico screening approach was employed using a large chemical database (ZINC database) containing over 2 million compounds.
- Computational methods were used to identify potential inhibitor candidates based on structural and chemical properties relevant to Bcl-2 family proteins.
Main Results:
- The in-silico screening successfully identified 17 sulfonamide derivatives with potential inhibitory activity against Bcl-2 family proteins.
- These identified compounds represent novel chemical entities for further investigation as anticancer drugs.
Conclusions:
- Sulfonamide derivatives show promise as potential inhibitors of anti-apoptotic Bcl-2 family proteins.
- The identified compounds warrant further biological evaluation to assess their efficacy in overcoming drug resistance and treating cancer.
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