A molecular mechanics model for imatinib and imatinib:kinase binding

Abstract

Imatinib is an important anticancer drug, which binds specifically to the Abl kinase and blocks its signalling activity. To model imatinib:protein interactions, we have developed a molecular mechanics force field for imatinib and four close analogues, which is consistent with the CHARMM force field for proteins and nucleic acids. Atomic charges and Lennard-Jones parameters were derived from a supermolecule ab initio approach. We considered the ab initio energies and geometries of a probe water molecule interacting with imatinib fragments at 32 different positions. We considered both a neutral and a protonated imatinib. The final RMS deviation between the ab initio and force field energies, averaged over both forms, was 0.2 kcal/mol. The model also reproduces the ab initio geometry and flexibility of imatinib. To apply the force field to imatinib:Abl simulations, it is also necessary to determine the most likely imatinib protonation state when it binds to Abl. This was done using molecular dynamics free energy simulations, where imatinib is reversibly protonated during a series of MD simulations, both in solution and in complex with Abl. The simulations indicate that imatinib binds to Abl in its protonated, positively-charged form. To help test the force field and the protonation prediction, we did MD free energy simulations that compare the Abl binding affinities of two imatinib analogs, obtaining good agreement with experiment. Finally, two new imatinib variants were considered, one of which is predicted to have improved Abl binding. This variant could be of interest as a potential drug.

Explaining why Gleevec is a specific and potent inhibitor of Abl kinase

“…This enables hydrogen-bonding interactions of Gleevec with the backbone carbonyl of specific residues in the binding pocket. The notion that Gleevec is protonated in the kinase-binding pockets is also supported by independent MD simulation studies (28).…”

“…This finding is further supported by the residual decomposition results that the P-loop, αC-helix, and A-loop of apo Abl significantly enhance the stabilization of the DFG motif in the inactive out conformation before binding Gleevec, relative to c-Src kinase. Conformational selection has been suggested as an explanation for the preference of Gleevec binding to Abl and c-Src (7,28,32,33).…”

Alchemical free energy simulations for biological complexes: powerful but temperamental …

“…87 On a slightly larger scale, we used it recently to add 12 tetracyclines to the CHARMM force field. 36,88 The most detailed calculations were done for ''plain'' tetracycline (Tc; shown in Figure 2): a neutral and a zwitterionic tautomer were considered, with an Mg 2þ ion present or absent.…”

Conformational landscape and low lying excited states of imatinib

“…Based on quantum chemical methods, recent works have addressed the interaction of IMT with Abl TK or calixarenes aiming at clarifying its mechanism of action [17][18][19][20][21] or at designing suitable drug carriers for TKIs [15,22]. For such purposes, the accurate description of the three-dimensional (3D) arrangement and molecular properties of thermally accessible conformational states is crucial [9,10,18,19,21,[23][24][25].…”

“…For such purposes, the accurate description of the three-dimensional (3D) arrangement and molecular properties of thermally accessible conformational states is crucial [9,10,18,19,21,[23][24][25]. Furthermore, analysis of the possible conformers of a particular drug molecule is mandatory for describing its spectroscopical properties reliably [26][27][28][29][30][31].…”