In silico Identification of Natural Compounds as Potential TrkA Inhibitors for Anticancer Drug Development

Area of Science:

• Oncology
• Pharmacology
• Computational Chemistry

Background:

• Tropomyosin receptor tyrosine kinase A (TrkA) is crucial for cancer cell migration and focal adhesion stability.
• Resistance to conventional TrkA inhibitors targeting the ATP-binding pocket poses a significant challenge in cancer therapy.
• Targeting TrkA signaling is vital for treating cancers with TrkA overexpression or mutation.

Purpose of the Study:

• To identify novel natural compounds as potential inhibitors of Tropomyosin receptor tyrosine kinase A (TrkA) for anticancer drug development.
• To evaluate the binding affinity and stability of identified natural compounds against TrkA.

Main Methods:

• Virtual screening of comprehensive natural compound libraries (NPACT and PhytoHub) using Schrödinger Desmond software.
• Molecular dynamics simulations and MM-GBSA free energy calculations to assess complex stability and binding affinity.
• Principal component analysis for in-depth simulation analysis.

Main Results:

• Two potent natural compounds, PHUB000399 and NPACT01417, were identified as TrkA inhibitors.
• PHUB000399 and NPACT01417 demonstrated superior binding affinities (grid scores: -13.239 and -13.103) compared to Entrectinib (-10.996).
• Molecular dynamics simulations confirmed enhanced stability for TrkA-PHUB000399 and TrkA-NPACT01417 complexes, with binding free energies of -87.74 and -86.09 kcal/mol, respectively.

Conclusions:

• NPACT01417 and PHUB000399 are promising candidates for developing novel anticancer therapies targeting TrkA.
• These natural compounds exhibit favorable binding characteristics and stability, comparable to established inhibitors.
• The findings provide a foundation for further investigation into TrkA-targeted cancer treatments.