Changing drug discovery one ratio of partition functions at a time
John Chodera publications
Mellinghoff I, Tang CP, Clark O, Ferrarone J, Campos C, Lalani AS, Chodera JD, Intlekofer AM, and Elemento O
Nature Chemical Biology}, 18:207, 2022 [DOI]
We describe paradoxical activation of GCN2 kinase activity by the kinase inhibitor neratinib, and propose a model for how inhibitor-induced dimerization might cause this unusual activity.
Steven K. Albanese, John D. Chodera, Andrea Volkamer, Simon Keng, Robert Abel, and Lingle Wang
Journal of Chemical Informatics and Modeling [DOI] [bioRxiv] [GitHub]
We asked whether the similarity of binding sites in related kinases might result in a fortuitous cancellation of errors in using alchemical free energy calculations to predict kinase inhibitor selectivities. Surprisingly, we find that even distantly related kinases have sufficient correlation in their errors that predicting changes in selectivity can be much more accurate than predicting changes in potency due to this effect, and show how this could lead to large reductions in the number of molecules that must be synthesized to achieve a desired selectivity goal.
Xu Jianing, Pham CG, Albanese SK, Dong Yiyu, Oyama T, Lee CH, Rodrik-Outmezguine V, Yao Z, Han S, Chen D, Parton DL, Chodera JD, Rosen N, Cheng EH, and Hsieh J. Journal of Clinical Investigation 126:3526, 2016. [DOI] [PDF]
In work with the James Hsieh lab at MSKCC, we examine the surprising origin of how different clinically-identified cancer-associated mutations in MTOR activate the kinase through distinct mechanisms.
