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Updated: Sep 22, 2025
Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
In silico SELEX screening and statistical analysis of newly designed 5mer peptide-aptamers as Bcl-xl inhibitors using
Alireza Poustforoosh1, Sanaz Faramarz2, Mohammad Hadi Nematollahi3
1Chemical Engineering Department, Faculty of Engineering, Shahid Bahonar University of Kerman, Kerman, Iran.
Abstract:
Drug development for cancer treatment is a complex process that requires special efforts. Targeting crucial proteins is the most essential purpose of drug design in cancers. Bcl-xl is an anti-apoptotic protein that binds to pro-apoptotic proteins and interrupts their signals. Pro-apoptotic Bcl-xl effectors are short BH3 sequences that form an alpha helix and bind to anti-apoptotic proteins to inhibit their activity. Computational systematic evolution of ligands by exponential enrichment (SELEX) is an exclusive approach for developing peptide aptamers as potential effectors. Here, the amino acids with a high tendency for constructing an alpha-helical structure were selected. Due to the enormous number of pentapeptides, Taguchi method was used to study a selected number of peptides. The binding affinity of the peptides to Bcl-xl was assessed using molecular docking, and after analysis of the obtained results, a final set of optimized peptides was arranged and constructed. For a better comparison, three chemical compounds with approved anti-Bcl-xl activity were selected for comparison with the top-ranked 5mer peptides. The optimized peptides showed considerable binding affinity to Bcl-xl. The molecular dynamics (MD) simulation indicated that the designed peptide (PO5) could create considerable interactions with the BH3 domain of Bcl-xl. The MM/GBSA calculations revealed that these interactions were even stronger than those created by chemical compounds. In silico SELEX is a novel approach to design and evaluate peptide-aptamers. The experimental design improves the SELEX process considerably. Finally, PO5 could be considered a potential inhibitor of Bcl-xl and a potential candidate for cancer treatment.
Insights
Researchers developed novel peptide aptamers targeting the anti-apoptotic protein Bcl-xl for cancer treatment. Computational SELEX identified a promising peptide, PO5, demonstrating strong binding affinity and potential as a Bcl-xl inhibitor.
Area of Science:
- Biochemistry
- Computational Biology
- Drug Discovery
Background:
- Targeting crucial proteins like Bcl-xl is essential in cancer drug development.
- Bcl-xl is an anti-apoptotic protein that inhibits programmed cell death.
- Pro-apoptotic BH3 sequences are natural effectors that bind and inhibit Bcl-xl.
Purpose of the Study:
- To design and evaluate novel peptide aptamers as potential Bcl-xl inhibitors using computational methods.
- To identify optimized peptides with high binding affinity to Bcl-xl for cancer therapy.
Main Methods:
- Computational Systematic Evolution of Ligands by Exponential Enrichment (SELEX) was employed.
- Amino acids with alpha-helical propensity were selected, and the Taguchi method optimized pentapeptides.
- Molecular docking, molecular dynamics (MD) simulations, and MM/GBSA calculations assessed binding affinity and interactions.
Main Results:
- Optimized peptides, particularly PO5, exhibited significant binding affinity to Bcl-xl.
- PO5 demonstrated strong interactions with the Bcl-xl BH3 domain, comparable or superior to approved anti-cancer drugs.
- In silico SELEX proved effective in designing and evaluating peptide aptamers.
Conclusions:
- The designed peptide PO5 is a potential inhibitor of Bcl-xl.
- PO5 represents a promising candidate for future cancer treatment development.
- Computational SELEX with experimental design enhances the discovery of novel therapeutic agents.
