# The role of reorganization energy in achieving selective kinase inhibition

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $352,465

## Abstract

PROJECT SUMMARY / ABSTRACT
The ability to rationally design small molecules that bind with high affinity and specificity to one or more biomolecu-
lar targets would radically transform drug discovery. Current approaches require many rounds of screening, mod-
eling, and synthesis in a trial-and-error approach that is costly, time-consuming, and ineffective. After decades
of work on the study of biomolecular interactions, there remains an enormous gulf between what we claim to un-
derstand about biomolecular association and our ability to put this knowledge into practice. This gulf is especially
wide for the design of selective kinase inhibitors, which aim to target one or more specific kinases in order to
effectively treat a disease—often cancer—and minimize unwanted toxic side effects.
While the discovery of imatinib was hailed as a breakthrough for its ability to selectively inhibit Abl despite the
existence of closely related kinases like Src, it came as a great surprise when the crystal structure of imatinib
bound to Src revealed that the Src:imatinib complex was nearly identical to Abl:imatinib. Recent evidence from
both experiments and modeling has suggested that a previously underappreciated contribution—the energetic
cost of populating the inhibitor-bound conformation—plays a critical role in the selectivity of imatinib for Abl over
Src. While this effect has only been studied in the well-studied case of Abl/Src binding to imatinib, it has the
potential to be much more general. We hypothesize that exploiting differences in the energetic cost of
confining related kinases to inhibitor binding-competent conformations may be a route to selectivity in
targeted kinase inhibition. Here, we ask how much conformational reorganization energy contributes to the
affinity of current FDA-approved noncovalent kinase inhibitors to determine whether existing inhibitors exploit
differences in these reorganization energies (perhaps inadvertently) to achieve selectivity, and whether there is a
clear route to exploiting this difference in rationally engineering new selective molecules.
We use a combined experimental and computational approach to decompose inhibitor binding affinity and se-
lectivity into contributions from kinase reorganization and binding to individual kinase conformations. We first
computationally map the conformations accessible to a diverse panel of human kinase catalytic domains, along
with their associated energetics. By using an automated fluorescence assay to measure the affinities of FDA-
approved noncovalent inhibitors to this panel and alchemical free energy calculations to determine the inhibitor
binding affinities to individual conformations, we can combine these data to quantify the relative contribution of
reorganization energy to the affinity and selectivity of kinase inhibition. We then use the introduction of point
mutants intended to modulate selectivity via reorganization energies to validate our model, and examine oppor-
tunities for...

## Key facts

- **NIH application ID:** 10241379
- **Project number:** 5R01GM121505-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** John Damon Chodera
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,465
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241379

## Citation

> US National Institutes of Health, RePORTER application 10241379, The role of reorganization energy in achieving selective kinase inhibition (5R01GM121505-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241379. Licensed CC0.

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