Design and evaluation of dual c-Met/β-tubulin inhibitors for triple-negative breast cancer: An In Silico approach

Area of Science:

• Computational chemistry and drug discovery
• Oncology and cancer therapeutics
• Pharmacology and toxicology

Background:

• Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options.
• The absence of hormone receptors and HER2 amplification characterizes TNBC, necessitating novel therapeutic strategies.
• Targeting multiple pathways simultaneously offers a promising approach for overcoming treatment resistance in TNBC.

Purpose of the Study:

• To establish an integrated computer-aided drug design (CADD) framework for identifying novel anti-TNBC agents.
• To discover dual inhibitors targeting both c-Met and β-tubulin, key pathways implicated in TNBC progression.
• To assess the in silico pharmacokinetic and safety profiles of potential drug candidates.

Main Methods:

• Development of robust conformation-independent quantitative structure-activity relationship (QSAR) models using SMILES and graph-based descriptors.
• Application of Monte Carlo optimization and CORAL-based validation for QSAR model reliability.
• Utilizing molecular docking simulations to evaluate binding affinities and interactions with c-Met and β-tubulin.
• In silico pharmacokinetic analysis to predict drug-likeness, absorption, metabolism, and toxicity.

Main Results:

• Highly predictive QSAR models achieved R² > 0.84 and Q²ext > 0.77, confirming reliability within the applicability domain.
• Identification of key molecular motifs associated with enhanced cytotoxicity against TNBC cells.
• Molecular docking revealed stable interactions and complementary binding modes for dual c-Met/β-tubulin inhibition.
• In silico pharmacokinetic profiling indicated favorable drug-likeness, good absorption, and low predicted toxicity.

Conclusions:

• The integrated CADD framework provides a rational approach for designing multitarget inhibitors against TNBC.
• Dual c-Met/β-tubulin inhibition represents a viable strategy for developing effective and safer therapies for TNBC.
• This study lays the groundwork for personalized therapeutic development in triple-negative breast cancer.