Prospective evaluation of structure-based simulations reveal their ability to predict the impact of kinase mutations on inhibitor binding

Sukrit Singh, Vytautas Gapsys, Matteo Aldeghi, David Schaller, Aziz M Rangwala, Jessica B White, Joseph P Bluck, Jenke Scheen, William G Glass, Jiaye Guo, Sikander Hayat, Bert L de Groot, Andrea Volkamer, Clara D Christ, Markus A Seeliger, John D Chodera.
[bioRxiv]

We show that alchemical free energy calculations have the potential to prospectively predict the impact of clinical kinase mutations on targeted kinase inhibitor binding.

Mutation in Abl kinase with altered drug binding kinetics indicates a novel mechanism of imatinib resistance

Agatha Lyczek, Benedict Tilman Berger, Aziz M Rangwala, YiTing Paung, Jessica Tom, Hannah Philipose, Jiaye Guo, Steven K Albanese, Matthew B Robers, Stefan Knapp, John D Chodera, Markus A Seeliger
Preprint ahead of publication: [bioRxiv]

Here, we characterize the biophysical mechanisms underlying mutants of Abl kinase associated with clinical drug resistance to targeted cancer therapies. We uncover a surprising novel mechanism of mutational resistance to kinase inhibitor therapy in which the off-rate for inhibitor unbinding is increased without affecting inhibitor affinity.

Predicting resistance of clinical Abl mutations to targeted kinase inhibitors using alchemical free-energy calculations

Kevin Hauser, Christopher Negron, Steven K. Albanese, Soumya Ray, Thomas Steinbrecher, Robert Abel, John D. Chodera, and Lingle Wang.
Communications Biology 1:70, 2018 [DOI] [PDF] [input files and analysis scripts]

In our first collaborative paper with Schrödinger, we present the first comprehensive benchmark assessing the ability for alchemical free energy calculations to predict clinical mutational resistance or susceptibility to targeted kinase inhibitors using the well-studied kinase Abl, the target of therapy for chronic myelogenous leukemia (CML).