2D-QSAR Modeling and Molecular Docking Studies on 1H-Pyrazole-1-carbothioamide Derivatives as EGFR Kinase Inhibitors

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Epidermal growth factor receptor (EGFR) kinase is implicated in various cancers, including lung, ovarian, prostate, colorectal, glioblastoma, pancreatic, and breast cancers.
• Developing targeted inhibitors for EGFR is a crucial strategy in cancer therapy.

Purpose of the Study:

• To perform quantitative structure-activity relationship (2D-QSAR) studies on 1H-pyrazole-1-carbothioamide derivatives to understand their EGFR kinase inhibitory activity.
• To design novel, potent EGFR kinase inhibitors based on established structure-activity relationships.

Main Methods:

• Construction and validation of 2D-QSAR models using partial least-squares (PLS) and stepwise multiple linear regression (SW-MLR).
• Validation employed leave-one-out (LOO) and external test set prediction.
• Molecular docking studies were conducted to predict interactions within the EGFR active site.

Main Results:

• Stepwise multiple linear regression (SW-MLR) yielded encouraging results, indicating adjacency distance matrix descriptors significantly influence EGFR inhibitory activity.
• Models were refined by removing outliers and defining an applicability domain.
• Eleven new, highly potent EGFR kinase inhibitor compounds were designed.

Conclusions:

• The study successfully established 2D-QSAR models for 1H-pyrazole-1-carbothioamide derivatives as EGFR kinase inhibitors.
• The findings provide insights into structural features essential for EGFR inhibition, guiding the design of novel anticancer agents.
• Designed compounds show promise as potential therapeutic candidates for EGFR-driven cancers.