G4-QuadScreen: A Computational Tool for Identifying Multi-Target-Directed Anticancer Leads against G-Quadruplex DNA.

Area of Science:

• Computational chemistry
• Drug discovery
• Bioinformatics

Background:

• G-quadruplexes (G4s) are non-canonical DNA structures implicated in various cellular processes, including cancer.
• Identifying small molecules that interact with and modulate G4 structures is a promising therapeutic strategy.
• Existing methods for G4-targeting drug discovery can be time-consuming and prone to false positives.

Purpose of the Study:

• To develop and validate a user-friendly computational tool, G4-QuadScreen, for identifying potential G4-targeting molecules.
• To predict G4 interaction, stabilization, selectivity, and cytotoxicity using multi-tasking Quantitative Structure-Activity Relationship (QSAR) models.
• To accelerate the early stages of drug discovery for G4-based therapeutics.

Main Methods:

• Development of multi-tasking QSAR models using linear discriminant analysis and random forest algorithms.
• Implementation of virtual screening using the G4-QuadScreen tool.
• Molecular docking simulations using YASARA and AutoDock-Vina.
• In vitro validation of G4 activities using FRET melting, Fluorescence Intensity Decay (FID), and cell viability assays.

Main Results:

• G4-QuadScreen models demonstrated high accuracy (>90% training, >80% external sets) in predicting G4 interactions and related properties.
• Virtual screening identified ten molecules with the capacity to selectively stabilize multiple G4 structures.
• Three of the screened molecules exhibited strong inhibitory effects on human cancer cell lines.
• Experimental validation confirmed the computational predictions for the identified molecules.

Conclusions:

• G4-QuadScreen is an effective computational tool for accelerating the discovery of novel G4-targeting drug leads.
• The tool aids in reducing false positive outcomes in the early stages of drug discovery.
• The identified molecules represent promising candidates for further development as anti-cancer agents targeting G4s.