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Author Spotlight: Characterizing DNA G-Quadruplex by Bis-3-Chloropiperidine Based Chemical Mapping
Published on: May 12, 2023
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G4-QuadScreen: A Computational Tool for Identifying Multi-Target-Directed Anticancer Leads against G-Quadruplex DNA.
Jyotsna Bhat-Ambure1, Pravin Ambure2, Eva Serrano-Candelas2
1MolDrug AI Systems SL, c/Olimpia Arozena Torres, 46018 Valencia, Spain.
Cancers
|August 12, 2023
Summary
G4-QuadScreen is a new computational tool that identifies potential drug candidates targeting G-quadruplexes (G4s). It successfully pinpointed several molecules that selectively stabilize G4s and inhibit cancer cell growth.
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.
