Steered molecular dynamics simulations reveal the likelier dissociation pathway of imatinib from its targeting kinases c-Kit and Abl

Abstract

Development of small molecular kinase inhibitors has recently been the central focus in drug discovery. And type II kinase inhibitors that target inactive conformation of kinases have attracted particular attention since their potency and selectivity are thought to be easier to achieve compared with their counterpart type I inhibitors that target active conformation of kinases. Although mechanisms underlying the interactions between type II inhibitors and their targeting kinases have been widely studied, there are still some challenging problems, for example, how type II inhibitors associate with or dissociate from their targeting kinases. In this investigation, steered molecular dynamics simulations have been carried out to explore the possible dissociation pathways of typical type II inhibitor imatinib from its targeting protein kinases c-Kit and Abl. The simulation results indicate that the most favorable pathway for imatinib dissociation corresponds to the ATP-channel rather than the relatively wider allosteric-pocket-channel, which is mainly due to the different van der Waals interaction that the ligand suffers during dissociation. Nevertheless, the direct reason comes from the fact that the residues composing the ATP-channel are more flexible than that forming the allosteric-pocket-channel. The present investigation suggests that a bulky hydrophobic head is unfavorable, but a large polar tail is allowed for a potent type II inhibitor. The information obtained here can be used to direct the discovery of type II kinase inhibitors.

Figure 1. Typical three-dimensional structures of protein kinases shown in Cα ribbon fashion.

(A) is for active conformation, and (B) for inactive conformation. Key structural components of the protein are color coded: A-loop in red, helix αC in purple, others in gray. Type I (for the active conformation) and type II (for the inactive conformation) kinase inhibitors are schematically shown in green wire mesh.

Figure 2. Chemical structure of imatinib and its binding modes to c-Kit and Abl.

(A) Chemical structure of imatinib. (B) 3D structure of imatinib-c-Kit complex (PDB entry: 1T46). (C) 3D structure of imatinib-Abl complex (PDB entry: 2HYY). In (B) and (C), protein structures are in Cα ribbon fashion and imatinib in green CPK fashion. Key structural components of the protein are color coded: A-loop in red, helix αC in purple, JMR in blue, others in gray.

Figure 3. RMSD (root mean square deviation) profiles of key motifs in imatinib-c-Kit complex during conventional molecular dynamics simulation.

The reference structure from which the RMSD was calculated is the crystal structure 1T46.

Figure 4. Force profiles of imatinib dissociation from imatinib-c-Kit complex.

(A) Force profile of imatinib unbinding along traditional ATP-channel. (B) Force profile of imatinib unbinding along allosteric-pocket-channel. (C) Averaged force profiles of imatinib unbinding along ATP-channel (red) and allosteric-pocket-channel (black).

Figure 5. RMSD (root mean square deviation) profiles of key motifs in imatinib-Abl complex during conventional molecular dynamics simulation.

The reference structure from which the RMSD was calculated is the crystal structure 2HYY.

Figure 6. Force profiles of imatinib dissociation from imatinib-Abl complex.

(A) Force profile of imatinib unbinding along ATP-channel. (B) Force profile of imatinib unbinding along allosteric-pocket-channel. (C) Averaged force profiles of imatinib unbinding along ATP-channel (red) and allosteric-pocket-channel (black).

Figure 7. Energy profiles of van der Waals (vdW) interaction between imatinib and its targeting kinases during dissociation.

(A) vdW interaction of imatinib-c-Kit system. (B) vdW interaction of imatinib-Abl system. The vdW profiles shown in solid line are for the ATP-channel and those shown in dotted line are for the allosteric-pocket-channel.

Figure 8. Variations of RMSD (root mean square deviation) values for the residues composing the ATP-channel (solid line) and allosteric-pocket-channel (dotted line) during the steered molecular dynamics simulations.

(A) is for imatinib-c-Kit system, and (B) for imaintib-Abl system.

Figure 9. Chemical structures of selected type II kinase inhibitors.

The substituent in dotted rectangle corresponds to the head of inhibitor and that in solid rectangle corresponds to the tail of inhibitor.