QSAR of Chalcones Utilizing Theoretical Molecular Descriptors

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Chalcone derivatives are investigated for their potential as anticancer agents.
• Understanding the structural basis of their activity is crucial for developing more effective drugs.
• Cell cycle inhibition, particularly at the G2/M phase, is a key mechanism for antiproliferative action.

Purpose of the Study:

• To develop Quantitative Structure-Activity Relationship (QSAR) models for a series of synthesized chalcone derivatives.
• To identify key molecular descriptors that correlate with the inhibition of the mitotic G2/M phase.
• To evaluate the predictive power of models based on different sets of descriptors.

Main Methods:

• Computed various molecular descriptors including topological, electrostatic, quantum chemical, constitutional, geometrical, and physicochemical indices.
• Employed multiple linear regression (MLR) and ridge regression (RR) for QSAR modeling.
• Validated the QSAR models using statistical metrics like R-squared and predicted R-squared (Rpred²).

Main Results:

• QSAR models demonstrated good predictive performance, with R² values up to 0.965 and QLoo² up to 0.891.
• Topological descriptors alone showed significant influence, while their combination with electrostatic and quantum chemical descriptors enhanced activity prediction.
• Key descriptors identified include BCUT descriptors (Charge) using modified partial equalization of orbital electronegativity (MPEOE), autocorrelation descriptors, information content descriptor, and HOMO descriptor.

Conclusions:

• The developed QSAR models provide valuable insights into the structural requirements for potent antimitotic and antiproliferative activities of chalcone derivatives.
• Specific descriptors like BCUT (Charge), autocorrelation, information content, and HOMO are critical for designing effective chalcone-based anticancer agents.
• These findings can guide the synthesis of novel chalcone compounds with improved efficacy in targeting the mitotic G2/M phase.