Design of New Second‐Generation TRK Inhibitors Targeting Tropomyosin Receptor Kinases by Using Molecular Docking, Molecular Dynamics Simulations and ADMET Properties

Abstract

TRK, as a type of cell surface protein, plays a critical role in various biological processes, particularly as a key target for cancer treatment. We explored the correlation between the structure and activity of indole‐2‐one derivatives through investigations involving 3D‐QSAR molecular modelling, molecular docking, molecular dynamics, and ADMET property research. The statistical data from the CoMFA and CoMSIA models exhibit excellent internal stability (CoMFA: q2=0.622, r2=0.992; CoMSIA: q2=0.740, r2=0.972). Further molecular docking unveiled the interaction mechanism between small molecules and receptor proteins, demonstrating that the hydrogen bonding between amino acids Met590 and Glu592 and small molecules could enhance the ligand‐receptor binding affinity. Based on the 3D‐QSAR model and molecular docking, we designed and predicted the activity of eight new molecules, which displayed high expected activity. Subsequently, through 100 ns MD simulations and binding free energy calculations, we affirmed the stability of the molecular docking results. Finally, we employed ADMET to predict the pharmacokinetic properties of the newly designed molecules, validating their commendable drug‐like characteristics. These research findings provide valuable references for the design and development of novel TRK inhibitors, offering fresh perspectives for subsequent drug design.