Micro-solvation of tyrosine-kinase inhibitor AG1478 explored with fluorescence spectroscopy and computational chemistry

Khattab, Muhammad; Wang, Feng; Clayton, Andrew H. A.

doi:10.1039/c7ra04435f

Cited by 5 publications

(6 citation statements)

References 59 publications

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“…A decrease in fluorescence due to an increase in temperature is expected based on an increase in the nonradiative rates of deactivation from the excited state or dynamic quenching processes. An increase in fluorescence with temperature is unusual but was reported by us previously for the AG1478–water complex in acetonitrile/water solutions because of a release of static quenching . This unorthodox temperature dependence of emission could be tentatively explained by both static and dynamic quenching mechanisms in the binding site of the protein or a temperature-dependent conformational change.…”

Section: Resultssupporting

confidence: 52%

“…An increase in fluorescence with temperature is unusual but was reported by us previously for the AG1478− water complex in acetonitrile/water solutions because of a release of static quenching. 53 This unorthodox temperature dependence of emission could be tentatively explained by both static and dynamic quenching mechanisms in the binding site of the protein or a temperature-dependent conformational change. However, we note that more work is needed to properly explain this behavior.…”

Section: Resultsmentioning

confidence: 98%

“…Five entries of AG1478 [four X-ray resolved structures + one calculated structure (entry 5)] were used with no further geometry optimization for calculating the excitation spectrum. Time-dependent density functional theory (TD-DFT) was used for excitation energy calculation using the same model and basis set employed for AG1478 in our previous published studies. − Becke three-parameter Lee–Yang–Parr hybrid functional , in combination with the 6-311+G* basis set and a conductor-like polarizable continuum model were employed in all calculations. Dielectric continuum of water (ε = 78.3) was used to approximately describe the polarity of the AG1478 environment.…”

Section: Methodsmentioning

confidence: 99%

“…AG1478 (Figure ) is a tyrosine kinase inhibitor, − and its electronic and conformational properties have been studied by our group. − Our studies revealed that the medium pH, polarity, and hydration significantly affect AG1478 conformation. We have also evaluated the topological and electronic properties of AG1478 under different conditions.…”

Section: Introductionmentioning

confidence: 92%

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Conformational Plasticity in Tyrosine Kinase Inhibitor–Kinase Interactions Revealed with Fluorescence Spectroscopy and Theoretical Calculations

Khattab¹,

Wang²,

Clayton³

2018

J. Phys. Chem. B

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To understand drug-protein dynamics, it is necessary to account for drug molecular flexibility and binding site plasticity. Herein, we exploit fluorescence from a tyrosine kinase inhibitor, AG1478, as a reporter of its conformation and binding site environment when complexed with its cognate kinase. Water-soluble kinases, aminoglycoside phosphotransferase APH(3')-Ia and mitogen-activated protein kinase 14 (MAPK14), were chosen for this study. On the basis of our prior work, the AG1478 conformation (planar or twisted) was inferred from the fluorescence excitation spectrum and the polarity of the AG1478-binding site was deduced from the fluorescence emission spectrum, while red-edge excitation shift (REES) probed the heterogeneity of the binding site (protein conformation and hydration) distributions in the protein conformational ensemble. In the AG1478-APH(3')-Ia complex, both twisted (or partially twisted) and planar AG1478 conformations were evidenced from emission wavelength-dependent excitation spectra. The binding site environment provided by APH(3')-Ia was moderately polar (λ = 480 nm) with evidence for considerable heterogeneity (REES = 34 nm). In contrast, in the AG1478-MAPK14 complex, AG1478 was in a predominantly planar conformation with a lower degree of conformational heterogeneity. The binding site environment provided by the MAPK14 protein was of relatively low polarity (λ = 430 nm) with a smaller degree of heterogeneity (REES = 11 nm). The results are compared with the available X-ray data and discussed in the context of our current understanding of tyrosine kinase inhibitor conformation and protein conformational ensembles.

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Section: Resultssupporting

confidence: 52%

Section: Resultsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

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Conformational Plasticity in Tyrosine Kinase Inhibitor–Kinase Interactions Revealed with Fluorescence Spectroscopy and Theoretical Calculations

Khattab¹,

Wang²,

Clayton³

2018

J. Phys. Chem. B

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“…Our own studies on AG1478 have revealed that the spectroscopic properties are sensitive to both environment 53 , 54 and AG1478 conformational state 55 . For example, two conformers- one planar and the other twisted- were identified based on quantum chemical calculations and experimental absorption spectra 55 .…”

Section: Introductionmentioning

confidence: 99%

A pH-induced conformational switch in a tyrosine kinase inhibitor identified by electronic spectroscopy and quantum chemical calculations

Khattab

Wang

Clayton

2017

Sci Rep

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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.

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Reinvestigation of the photophysics of 3-aminobenzoic acid in neat and mixed binary solvents

Husain

Mehata

Pandey

et al. 2021

Spectrochimica Acta Part A: Molecular and Biomolecular Spectros

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Micro-solvation of tyrosine-kinase inhibitor AG1478 explored with fluorescence spectroscopy and computational chemistry

Abstract: Fluorescence quenching of the anticancer AG1478, by at least three explicit water molecules, can be exploited to probe drug–protein binding interactions.

Cited by 5 publications

References 59 publications

Conformational Plasticity in Tyrosine Kinase Inhibitor–Kinase Interactions Revealed with Fluorescence Spectroscopy and Theoretical Calculations

Conformational Plasticity in Tyrosine Kinase Inhibitor–Kinase Interactions Revealed with Fluorescence Spectroscopy and Theoretical Calculations

A pH-induced conformational switch in a tyrosine kinase inhibitor identified by electronic spectroscopy and quantum chemical calculations

Reinvestigation of the photophysics of 3-aminobenzoic acid in neat and mixed binary solvents

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