Investigation on the binding mechanism of loratinib with the c-ros oncogene 1 (ROS1) receptor tyrosine kinase via molecular dynamics simulation and binding free energy calculations

Abstract

The c-ros oncogene 1 (ROS1) has proven to be an important cancer target for the treatment of various human cancers. The anaplastic lymphoma kinase inhibitor crizotinib has been granted approval for the treatment of patients with ROS1 positive metastatic non-small-cell lung cancer by the Food and Drug Administration on 2016. However, serious resistance due to the secondary mutation of glycine 2032 to arginine (G2032R) was developed in clinical studies. Loratinib (PF-06463922), a macrocyclic analog of crizotinib, showed significantly improved inhibitory activity against wild–type (WT) ROS1 and ROS1^G2032R mutant. To provide insights into the inhibition mechanism, molecular dynamics simulations and free energy calculations were carried out for the complexes of loratinib with WT and G2032R mutated ROS1. The apo-ROS1^WT and apo-ROS1^G2032R systems showed similar RMSF distributions, while ROS1^G2032R-loratinib showed significantly higher than that of WT ROS1-loratinib, which revealed that the binding of loratinib to ROS1^G2032R significantly interfered the fluctuation of protein. Calculations of binding free energies indicate that G2032R mutation significantly reduces the binding affinity of loratinib for ROS1, which arose mostly from the increase of conformation entropy and the decrease of solvation energy. Furthermore, detailed per-residue binding free energies highlighted the increased and decreased contributions of some residues in the G2032R mutated systems. The present study revealed the detailed inhibitory mechanism of loratinib as potent WT and G2032R mutated ROS1 inhibitor, which was expected to provide a basis for rational drug design.

Keywords:

• molecular dynamics (MD)
• binding free energy calculation
• ROS1 inhibitor
• loratinib

Abbreviations:

• c-ros oncogene 1 (ROS1)
• anaplastic lymphoma kinase (ALK)
• non-small-cell lung cancer (NSCLC)
• Food and Drug Administration (FDA)
• mutation of glycine 2032 to arginine (G2032R)
• wide-type (WT)
• molecular dynamics (MD)
• molecular mechanics Poisson-Boltzmann surface area (MM-PBSA)
• molecular mechanics generalized born surface area (MM-GBSA)
• protein data bank (PDB)
• restrained electrostatic potential (RESP)
• GAFF (general AMBER force field)
• transferable interaction potential (TIP3P)
• particle mesh Ewald (PME)
• solvent-accessible surface area (SASA)

Acknowledgements

We are thankful to the Scientific Computing Grid (ScGrid) of Supercomputing Center of Chinese Academy of Science.