Design of novel anti-cancer drugs targeting TRKs inhibitors based 3D QSAR, molecular docking and molecular dynamics...

Area of Science:

• Medicinal Chemistry
• Computational Drug Design
• Oncology

Background:

• Tropomyosin receptor kinase (TRK) enzymes, implicated in various cancers due to gene fusions, are crucial therapeutic targets.
• Developing potent and selective TRK inhibitors is essential for effective anticancer strategies.

Purpose of the Study:

• To design and identify novel pyrazol-based inhibitors with high anticancer activity against TRK enzymes.
• To elucidate the structure-activity relationships (SAR) of these inhibitors using computational methods.

Main Methods:

• Employed 3D-QSAR (HQSAR, CoMFA, CoMSIA/SE, Topomer CoMFA) for quantitative structure-activity relationship modeling.
• Utilized molecular docking and molecular dynamics (MD) simulations to analyze binding interactions and stability.
• Validated models through external validation and predicted physicochemical and ADME-Tox properties.

Main Results:

• Established highly reliable and predictable QSAR models (HQSAR: Q²=0.793, R²=0.917; Topomer CoMFA: Q²=0.726, R²=0.992).
• Identified key active site residues (Met 592, Glu 590, Leu 657, Val 524, Phe 589) for TRK inhibition.
• Compound 19i demonstrated stable complex formation with TRK (PDB ID: 5KVT); newly designed compounds showed promising predicted activity, oral bioavailability, and non-toxicity.

Conclusions:

• The developed computational models provide valuable structural insights for designing potent TRK type I inhibitors.
• The study successfully identified promising lead compounds with favorable drug-like properties for further experimental investigation.
• This research offers a rational approach to accelerate the discovery of novel TRK-targeted anticancer agents.