Dual Targeting of CXCR4 and CXCL12 by 1,2,4-Triazole Derivatives: A Computational Approach Against Lung Cancer...

Migration of lung cancer cells to distant sites is largely mediated by the CXCR4/CXCL12 axis. Meanwhile, 1,2,4-triazole derivatives have shown antiproliferative activity in lung cancer and have been reported to inhibit metastasis in pancreatic and breast cancer.

This study aimed to screen 1,2,4-triazole derivatives with high potential to target the CXCR4/CXCL12 axis associated with lung cancer metastasis using multiple computational methods.

A total of 79 1,2,4-triazole derivatives were screened using ligand-based pharmacophore modeling (LigandScout Essential 4.4.9) and molecular docking (AutoDock 4.2.6). Molecular dynamics (MD) simulations were then performed using GROMACS 2021.4 to further characterize protein-ligand interactions. Finally, compound safety, biological behavior, and drug-development feasibility were evaluated using toxicity prediction (ProTox 3.0) and pharmacokinetic and drug-likeness assessments (pkCSM).

Sixteen derivatives (D41-D51 and D53-D57) matched the CXCR4 and CXCL12 pharmacophore models. The CXCR4 model (model 8) comprised two hydrophobic features, one aromatic ring, and one hydrogen bond donor, whereas the CXCL12 model (model 3) included one hydrophobic feature, two aromatic rings, and three hydrogen bond acceptors. Docking studies against CXCR4 and CXCL12 indicated that D54 and D57 had more favorable predicted docking scores than mavorixafor (a CXCR4 inhibitor) and LIT-927 (a CXCL12 inhibitor). These findings were supported by MD simulations, as indicated by stable root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), hydrogen bond (H-bond) occupancy, and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) results. Toxicity and pharmacokinetic predictions suggested that D54 and D57 had both favorable properties and potential liabilities.

Compounds D54 and D57 were computationally prioritized as promising 1,2,4-triazole derivatives targeting the CXCR4/CXCL12 axis for further investigation in lung cancer metastasis. However, their predicted toxicity, pharmacokinetic, and drug-likeness profiles revealed several limitations that warrant further optimization and experimental validation.