In-silico probing of AML related RUNX1 cancer-associated missense mutations: Predicted relationships to DNA binding
Hanif Ullah1,2,3, Baoyun Zhang2,3, Narendra Kumar Sharma4
1Guangxi Key Laboratory for Genomics and Personalized Medicine, Guangxi Collaborative Innovation Center for Genomics and Personalized Medicine, Guangxi Medical University, Nanning, China.
Abstract:
The molecular consequences of cancer associated mutations in Acute myeloid leukemia (AML) linked factors are not very well understood. Here, we interrogated the COSMIC database for missense mutations associated with the RUNX1 protein, that is frequently mis-regulated in AML, where we sought to identify recurrently mutated positions at the DNA-interacting interface. Indeed, six of the mutated residues, out of a total 417 residues examined within the DNA binding domain, evidenced reduced DNA association in in silico predictions. Further, given the prominence of RUNX1's compromised function in AML, we asked the question if the mutations themselves might alter RUNX1's interaction (off-target) with known FDA-approved drug molecules, including three currently used in treating AML. We identified several AML-associated mutations in RUNX1 that were calculated to enhance RUNX1's interaction with specific drugs. Specifically, we retrieved data from the COSMIC database for cancer-associated mutations of RUNX1 by using R package "data.table" and "ggplot2" modules. In the presence of DNA and/or drug, we used docking scores and energetics of the complexes as tools to evaluate predicted interaction strengths with RUNX1. For example, we performed predictions of drug binding pockets involving Enasidenib, Giltertinib, and Midostaurin (AML associated), as well as ten different published cancer associated drug compounds. Docking of wild type RUNX1 with these 13 different cancer-associated drugs indicates that wild-type RUNX1 has a lower efficiency of binding while RUNX1 mutants R142K, D171N, R174Q, P176H, and R177Q suggested higher affinity of drug association. Literature evidence support our prediction and suggests the mutation R174Q affects RUNX1 DNA binding and could lead to compromised function. We conclude that specific RUNX1 mutations that lessen DNA binding facilitate the binding of a number of tested drug molecules. Further, we propose that molecular modeling and docking studies for RUNX1 in the presence of DNA and/or drugs enables evaluation of the potential impact of RUNX1 cancer associated mutations in AML.
Insights
Cancer mutations in RUNX1, a protein linked to Acute Myeloid Leukemia (AML), can alter its DNA binding and drug interactions. Specific RUNX1 mutations may enhance binding to AML drugs, impacting treatment effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Acute Myeloid Leukemia (AML) is often associated with dysregulated RUNX1 protein function.
- The precise molecular impact of cancer-associated mutations in RUNX1 remains incompletely understood.
- RUNX1 mutations can affect its DNA-binding capabilities and interactions with other molecules.
Purpose of the Study:
- To investigate the effects of RUNX1 missense mutations on DNA interaction and drug binding.
- To identify specific RUNX1 mutation sites within the DNA-binding domain.
- To evaluate how AML-associated RUNX1 mutations influence interactions with FDA-approved AML drugs.
Main Methods:
- Interrogation of the COSMIC database for RUNX1 mutations.
- In silico prediction of DNA binding affinity for mutated RUNX1 residues.
- Molecular docking studies to assess RUNX1-drug interactions using scoring and energetics.
- Analysis of binding affinities for wild-type and mutant RUNX1 with 13 cancer-associated drugs, including three used in AML treatment.
Main Results:
- Six recurrently mutated residues in the RUNX1 DNA-binding domain showed reduced DNA association in silico predictions.
- Several RUNX1 mutants exhibited enhanced predicted binding affinity to specific drugs compared to wild-type RUNX1.
- Mutants R142K, D171N, R174Q, P176H, and R177Q showed higher predicted affinity for drug association.
- Literature supports that the R174Q mutation impacts RUNX1 DNA binding and function.
Conclusions:
- Specific RUNX1 mutations associated with AML can decrease DNA binding while increasing interaction with certain drug molecules.
- Molecular modeling and docking are valuable tools for evaluating the impact of RUNX1 mutations on drug interactions in AML.
- Understanding these altered interactions is crucial for assessing the efficacy of AML therapies targeting RUNX1.
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