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Published on: November 11, 2016
A pH-induced conformational switch in a tyrosine kinase inhibitor identified by electronic spectroscopy and quantum
Muhammad Khattab1, Feng Wang2,3,4, Andrew H A Clayton5
1Centre for Micro-Photonics, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Melbourne, Victoria, 3122, Australia.
Abstract:
Tyrosine kinase inhibitors (TKIs) are a major class of drug utilised in the clinic. During transit to their cognate kinases, TKIs will encounter different pH environments that could have a major influence on TKI structure. To address this, we report UV-Vis spectroscopic and computational studies of the TKI, AG1478, as a function of pH. The electronic absorption spectrum of AG1478 shifted by 10 nm (from 342 nm to 332 nm) from acid to neutral pH and split into two peaks (at 334 nm and 345 nm) in highly alkaline conditions. From these transitions, the pKa value was calculated as 5.58 ± 0.01. To compute structures and spectra, time-dependent density functional theory (TD-DFT) calculations were performed along with conductor-like polarizable continuum model (CPCM) to account for implicit solvent effect. On the basis of the theoretical spectra, we could assign the AG1478 experimental spectrum at acidic pH to a mixture of two twisted conformers (71% AG1478 protonated at quinazolyl nitrogen N(1) and 29% AG1478 protonated at quinazolyl nitrogen N(3)) and at neutral pH to the neutral planar conformer. The AG1478 absorption spectrum (pH 13.3) was fitted to a mixture of neutral (70%) and NH-deprotonated species (30%). These studies reveal a pH-induced conformational transition in a TKI.
Insights
Tyrosine kinase inhibitors (TKIs) undergo structural changes with pH. This study reveals pH-induced conformational transitions in the TKI AG1478, impacting its electronic absorption spectrum and structure.
Area of Science:
- Biochemistry
- Chemical Physics
- Medicinal Chemistry
Background:
- Tyrosine kinase inhibitors (TKIs) are crucial in clinical treatments.
- TKIs encounter varying pH environments during drug delivery, potentially altering their structure.
- Understanding pH-dependent TKI behavior is vital for drug efficacy.
Purpose of the Study:
- To investigate the pH-dependent structural and spectral properties of the TKI AG1478.
- To elucidate the conformational changes of AG1478 across different pH conditions.
- To determine the pKa value of AG1478 and its implications.
Main Methods:
- UV-Vis spectroscopy was employed to monitor spectral changes of AG1478 at varying pH.
- Time-dependent density functional theory (TD-DFT) calculations were performed.
- The conductor-like polarizable continuum model (CPCM) was used to simulate solvent effects.
Main Results:
- AG1478 exhibited a 10 nm spectral shift from acidic to neutral pH.
- In alkaline conditions, the spectrum split, indicating distinct species.
- The calculated pKa value for AG1478 was 5.58 ± 0.01.
- Computational analysis assigned spectra to protonated and neutral conformers.
Conclusions:
- AG1478 undergoes significant pH-induced conformational transitions.
- Protonation states and conformers vary with pH, affecting spectral properties.
- These findings highlight the importance of pH in TKI drug design and delivery.
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