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.

Identifying and Overcoming the Sampling Challenges in Relative Binding Free Energy Calculations of a Model Protein:Protein Complex

Zhang I, Rufa DA, Pulido I, Henry MM, Rosen LE, Hauser K, Singh S, Chodera JD
Journal of Chemical Theory and Computation 19:4863, 2023

We assess what is required for alchemical free energy calculations to be able to make high-quality predictions of the impact of interfacial mutations on protein-protein binding.

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).