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Commun Biol. 2018;1. pii: 70. doi: 10.1101/239012. Epub 2018 Jun 13.

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

Author information

1
Schrödinger, New York, NY 10036.
2
Gerstner Sloan Kettering Graduate School, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
3
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
4
Schrödinger, GmbH, Q7 23, 68161 Mannheim, Germany.

Abstract

The therapeutic effect of targeted kinase inhibitors can be significantly reduced by intrinsic or acquired resistance mutations that modulate the affinity of the drug for the kinase. In cancer, the majority of missense mutations are rare, making it difficult to predict their impact on inhibitor affinity. This complicates the practice of precision medicine, pairing of patients with clinical trials, and development of next-generation inhibitors. Here, we examine the potential for alchemical free-energy calculations to predict how kinase mutations modulate inhibitor affinities to Abl, a major target in chronic myelogenous leukemia (CML). We find these calculations can achieve useful accuracy in predicting resistance for a set of eight FDA-approved kinase inhibitors across 144 clinically-identified point mutations, achieving a root mean square error in binding free energy changes of 1.10.91.3 kcal/mol (95% confidence interval) and correctly classifying mutations as resistant or susceptible with 888293% accuracy. Since these calculations are fast on modern GPUs, this benchmark establishes the potential for physical modeling to collaboratively support the rapid assessment and anticipation of the potential for patient mutations to affect drug potency in clinical applications.

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