Binding studies of caffeine and theophylline to bovine serum albumin: Calorimetric and spectroscopic approach

Banipal, Tarlok S.; Kaur, Navalpreet; Banipal, Parampaul K.

doi:10.1016/j.molliq.2016.09.034

Cited by 21 publications

(11 citation statements)

References 16 publications

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“…32 There are previous works that described positive ΔC p thermodynamics for the protein−small ligand interactions; the positive heat capacity change is thought to result when the ligand binds to an exposed nonpolar surface. 36,37 Based on the model structures, we calculated the solvent-accessible surface area (ASA) of Hsp90 in each complex. As shown in Table 1, the nonpolar and polar ASAs of Hsp90 in the THS-510 complex (5809.7 and 4979.4 Å 2 ) were larger than those in the TAS-116 complex (5785.9 and 4900.9 Å 2 ), respectively.…”

Section: ■ Resultsmentioning

confidence: 99%

Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors

et al. 2021

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The cytosolic Hsp90-selective inhibitor TAS-116 has an acceptable safety profile and promising antitumor activity in clinical trials. We examined the binding characteristics of TAS-116 and its analogs to determine the impact of the ligand binding mode on selectivity for cytosolic Hsp90. Analyses of the co-crystal structure of Hsp90 and inhibitor TAS-116 suggest that TAS-116 interacts with the ATP-binding pocket, the ATP lid region, and the hydrophobic pocket. A competitive isothermal titration calorimetry analysis confirmed that a small fragment of TAS-116 (THS-510) docks into the lid region and hydrophobic pockets without binding to the ATP-binding pocket. THS-510 exhibited enthalpy-driven binding to Hsp90α and selectively inhibited cytosolic Hsp90 activity. The heat capacity change of THS-510 binding was positive, likely due to the induced conformational rearrangement of Hsp90. Thus, we concluded that interactions with the hydrophobic pocket of Hsp90 determine potency and selectivity of TAS-116 and derivatives for the cytosolic Hsp90 isoform.

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Section: ■ Resultsmentioning

confidence: 99%

Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors

et al. 2021

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“…These observations primarily indicated perturbation in the microenvironment during ground-state complex formation. 39,40 The binding constant value ( K ) was obtained from the method as described by Benesi and Hildebrand, 41 using a double reciprocal plot based on the equation: Here, A obs is absorbance of HSA solution with variable concentrations of AG at 278 nm. A o and A c are the absorbance values for HSA and HSA–AG complexes.…”

Section: Resultsmentioning

confidence: 99%

Section: Characterization Of Binding Interaction Between Hsa and Agmentioning

confidence: 99%

Andrographolide inhibits human serum albumin fibril formations through site-specific molecular interactions

et al. 2018

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“…For example, the binding and interaction of caffeine with lysozyme have been reported to induce conformational changes in lysozyme . Due to hydrophilic–ionic and hydrogen bonding interactions with BSA, the binding of caffeine and BSA causes the deshielding of caffeine protons . The crystal structure of bacterial N -demethylase with caffeine bound is recently solved .…”

Section: Discussionmentioning

confidence: 99%

Investigating Crystalline Protein Suspension Formulations of Pembrolizumab from MAS NMR Spectroscopy

Reichert

Narasimhan

et al. 2022

Mol. Pharmaceutics

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Developing biological formulations to maintain the chemical and structural integrity of therapeutic antibodies remains a significant challenge. Monoclonal antibody (mAb) crystalline suspension formulation is a promising alternative for high concentration subcutaneous drug delivery. It demonstrates many merits compared to the solution formulation to reach a high concentration at the reduced viscosity and enhanced stability. One main challenge in drug development is the lack of high-resolution characterization of the crystallinity and stability of mAb microcrystals in the native formulations. Conventional analytical techniques often cannot evaluate structural details of mAb microcrystals in the native suspension due to the presence of visible particles, relatively small crystal size, high protein concentration, and multicomponent nature of a liquid formulation. This study demonstrates the first high-resolution characterization of mAb microcrystalline suspension using magic angle spinning (MAS) NMR spectroscopy. Crystalline suspension formulation of pembrolizumab (Keytruda, Merck & Co., Inc., Kenilworth, NJ 07033, U.S.) is utilized as a model system. Remarkably narrow 13 C spectral linewidth of approximately 29 Hz suggests a high order of crystallinity and conformational homogeneity of pembrolizumab crystals. The impact of thermal stress and dehydration on the structure, dynamics, and stability of these mAb crystals in the formulation environment is evaluated. Moreover, isotopic labeling and heteronuclear 13 C and 15 N spectroscopies have been utilized to identify the binding of caffeine in the pembrolizumab crystal lattice, providing molecular insights into the cocrystallization of the protein and ligand. Our study provides valuable structural details for facilitating the design of crystalline suspension formulation of Keytruda and demonstrates the high potential of MAS NMR as an advanced tool for biophysical characterization of biological therapeutics.

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Binding studies of caffeine and theophylline to bovine serum albumin: Calorimetric and spectroscopic approach

Cited by 21 publications

References 16 publications

Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors

Thermodynamic Dissection of Potency and Selectivity of Cytosolic Hsp90 Inhibitors

Andrographolide inhibits human serum albumin fibril formations through site-specific molecular interactions

Investigating Crystalline Protein Suspension Formulations of Pembrolizumab from MAS NMR Spectroscopy

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