Gain of native conformation of Aurora A S155R mutant by small molecules

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Drug Discovery

Background:

• Aurora A kinase is a key mitotic regulator overexpressed in various human cancers, making it a prime target for anticancer drug design.
• A specific somatic mutation, S155R, in Aurora A disrupts its interaction with TPX2, leading to uncontrolled cell proliferation, chromosome instability, and oncogenic transformation.
• Restoring the S155R mutant's interaction with TPX2 is a therapeutic strategy to counteract its oncogenic effects.

Purpose of the Study:

• To identify a drug molecule capable of restoring the interaction between the S155R Aurora A mutant and its binding partner, TPX2.
• To computationally screen and validate potential therapeutic agents for targeting the S155R Aurora A mutation.

Main Methods:

• Computational approaches including hotspot mapping for uncompetitive binding, virtual screening, protein-ligand docking, and protein-protein docking.
• Validation of identified drug candidates through computational analysis.

Main Results:

• The study screened and validated ZINC968264 as a molecule that can potentially reverse the loss-of-function caused by the S155R mutation in Aurora A.
• ZINC968264 demonstrated potential in restoring the interaction between the S155R Aurora A mutant and TPX2.

Conclusions:

• The developed computational methodology provides a viable strategy for designing drugs targeting the S155R Aurora A mutant.
• ZINC968264 represents a promising lead compound for developing novel anticancer therapeutics aimed at correcting Aurora A dysfunction in cancer.