Objective

Protein kinases are one of the most important families of drug targets for the pharmaceutical industry, and, although the number of FDA-approved kinase drugs continues to increase, finding drug molecules that effectively and selectively target these systems remains a great challenge. A critical component, one that is not unique to kinases, yet so far has not been systematically exploited, is the role of conformational dynamics in the process of drug binding. Anton, a specialized supercomputer for performing molecular dynamics simulations, has enabled simulations on the micro- to millisecond timescale, which are long enough to capture the details of protein conformational rearrangements and drug binding. Anton simulations have been used not only to visualize the complete binding process of kinase drugs such as lapatinib, gefitinib, and dasatinib, but also to follow critical protein kinase conformational changes such as the DFG flip and the rearrangement of the activation loop. Conformational dynamics can also help to elucidate functional differences, as in the case of EGFR, where cancer mutants appear to “over-stabilize” EGFR kinase relative to wild type, thereby promoting dimerization that leads to aberrant activation. Another promising direction is the use of long-timescale simulations to discover cryptic binding sites, features that may be absent from crystal structures but useful in the development of selective kinase inhibitors