Related Experiment Video
Updated: Aug 23, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
An in silico analysis of the impact of POLE mutations on cladribine docking
L Loganathan1, A Al-Haidose, A Ganesh Kumar
1Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, India. aabdallah@qu.edu.qa.
Objective:
Polymerase ε exonuclease (POLE) is an enzyme involved in DNA replication and may be an attractive therapeutic target in various cancers. Here we sought to model the impact of specific POLE mutations on protein function. Due to the lack of a crystal structure, the tertiary structures of the wild type and four common mutants were modeled using I-Tasser server.
Materials And Methods:
Molecular docking and dynamic simulation studies were performed, and the structure and function of the mutants analyzed through residue conservation analysis and protein folding energy changes.
Results:
All mutants of POLE gene had favorable binding affinities compared with their wild type of counterpart. The P286R variant, but not the other variants, disrupted cladribine binding to the protein. Similarly, dynamics studies revealed instability of the P286R mutant, while V411L, L424V, and L424F appeared to favor cladribine binding.
Conclusions:
Since P286R is a hotspot mutation in endometrioid carcinomas, patients with this variant may not respond to cladribine. Population-based pharmacogenomics studies will be required to validate our results.
Insights
Specific POLE mutations impact DNA repair enzyme function and drug binding. The P286R mutation may hinder cladribine effectiveness in cancer patients, necessitating further pharmacogenomic studies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapeutics
Background:
- Polymerase ε exonuclease (POLE) is crucial for DNA replication and a potential cancer therapeutic target.
- Understanding POLE mutations is key to developing effective cancer treatments.
Purpose of the Study:
- To model the functional impact of specific POLE mutations.
- To investigate how POLE mutations affect protein structure and drug interactions.
Main Methods:
- Tertiary structures of wild-type POLE and four mutants were modeled using I-Tasser.
- Molecular docking, dynamic simulations, residue conservation analysis, and protein folding energy changes were employed.
Main Results:
- All POLE mutants showed favorable binding affinities compared to wild-type.
- The P286R mutation disrupted cladribine binding and caused instability.
- V411L, L424V, and L424F variants appeared to enhance cladribine binding.
Conclusions:
- The P286R mutation, a hotspot in endometrioid carcinomas, may confer resistance to cladribine.
- Further population-based pharmacogenomic studies are needed to validate these findings.
More Related Videos
10:33Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
Published on: October 26, 2015
05:08Application of I TASSER, trRosetta, UCSF Chimera, HADDOCK server, and HEX loria for De Novo and In Silico Design of Proteins
Published on: July 8, 2025
Related Concept Videos
01:16In-vitro Mutagenesis
01:16Protein-Drug Binding: Mechanism and Kinetics
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...