Molecular recognition of tak-285 and lapatinib by inactive, active, and middle active-inactive HER2.

Experimental and theoretical studies have provided structural information regarding the shift from inactive to active EGFR, throughout which both conformations are linked via binding to specific tyrosine kinase inhibitors. For HER2, an intermediate active-inactive receptor conformation is present in the PDB, which has been co-crystallized with tak-285. The affinity of HER2 in monomeric state to tak-285 has been previously reported. However, the lack of structural knowledge of HER2 limits our capacity to understand whether tak-285, or other known HER2 inhibitors, selectively bind active, inactive, or intermediate forms of HER2. To elucidate mechanisms by which tak-285 binds to HER2, we first obtained information regarding the structural features of the active state of HER2 via microsecond MD simulations from the crystallized intermediate structure previously determined. Based on these HER2 conformers, together with the inactive HER2 conformer obtained in a previous study, we used docking and MD simulations coupled to MMGBSA approach to assess binding of tak-285 and lapatinib, known HER2/EGFR dual inhibitors, to HER2. Structural and energetic studies revealed that tak-285 binds with a greater affinity than lapatinib to active and intermediate active-inactive forms of HER2. This is in accordance with experimental findings that showed the tak-285 inhibitor has increased activity relative to lapatinib in breast cancer cell lines.