Binding of the B-Raf Inhibitors Dabrafenib and Vemurafenib to Human Serum Albumin: A Biophysical and Molecular Simulation Study

Russi, Maria; Cavalieri, Gabriele; Laurini, Erik; Pricl, Sabrina

doi:10.1021/acs.molpharmaceut.2c00100

Cited by 6 publications

(6 citation statements)

References 101 publications

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“…The negative and positive values of Δ H 0 and Δ S 0 respectively describe the formation of the mucin–bioactive complex, suggesting that electrostatic/ionic forces of interaction are predominantly involved in the stabilization of the mucin–bioactive complex. Notably, the magnitude of Δ S 0 was greater than that of Δ H 0 in both cases, indicating that the mucin–bioactive interactions are entropy-driven and not enthalpy-driven …”

Section: Discussionmentioning

confidence: 85%

“…Notably, the magnitude of ΔS 0 was greater than that of ΔH 0 in both cases, indicating that the mucin−bioactive interactions are entropy-driven and not enthalpy-driven. 49 CD spectroscopy is a powerful tool to investigate the protein conformation in solution during the association of proteins with other ligands. The increase in the negative band indicates that the structure of the mucin−bioactive complex is more compact than that of pure mucin and thus is consistent with previous reports.…”

Section: ■ Discussionmentioning

confidence: 99%

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Bioactives Promiscuity of Mucin: Insight from Multi-Spectroscopic, Thermodynamic, and Molecular Dynamic Simulation Analyses

et al. 2023

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Mucosal drug delivery plays an increasing role in the clinical setting owing to mucin's advantageous biochemical and pharmacological properties. However, how this transport system recognizes different substrates remains unclear. In this study, we explore the mechanism of bioactive (quercetin and berberine) promiscuity of mucin using various spectroscopic techniques and molecular dynamics simulations. The UV−visible spectroscopy results and the decreased fluorescence intensity of mucin in the presence of the bioactive compounds via a static quenching mechanism confirmed ground-state complex formation between the bioactives and mucin. The binding constants (K b ) were evaluated at different temperatures to afford K b values of ∼10 4 Lmol −1 , demonstrating the moderate and reasonable affinity of the bioactives for mucin, yielding greater diffusion into the tissues. Thermodynamic analysis and molecular dynamics (MD) simulations demonstrate that mucin−bioactive complex formation occurs primarily because of electrostatic/ionic interactions, while hydrophobic interactions were also crucial in stabilizing the complex. Far-UV circular dichroism spectroscopy showed that bioactive binding induced secondary structural changes in mucin. Sitemap and MD simulation indicated the principal binding site of mucin for the bioactives. This study also provides insight into the bioactives promiscuity of mucin in the presence of a crowded environment, which is relevant to the biological activity of mucin in vivo. An in vitro drug release study revealed that crowding assisted drug release in an enhanced burst manner compared with that in a dilute buffer system. This work thus provides fresh insight into drug absorption and distribution in the native cellular environment and helps direct new drug design and use in pharmaceutical and pharmacological fields.

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Section: Discussionmentioning

confidence: 85%

Section: ■ Discussionmentioning

confidence: 99%

Bioactives Promiscuity of Mucin: Insight from Multi-Spectroscopic, Thermodynamic, and Molecular Dynamic Simulation Analyses

et al. 2023

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“…Many of the studies in the past few years could predict second to hour time scale dissociation kinetics of drug-like molecules within 1 order of magnitude accuracy ,,,,,, (Figure b). Although this is promising, the amount of computational effort invested in such calculations (including the time spent on system-specific CV discovery) prevented their large-scale adoption in the pharmaceutical industry.…”

Section: Applicationsmentioning

confidence: 99%

“…The success of this approach depends on a correct choice of θ, which, however, is nontrivial and requires some amount of trial and error. Nevertheless, FA-MetaD has been used for estimating the kinetics of protein–ligand unbinding. − …”

Section: Theoretical Backgroundmentioning

confidence: 99%

Kinetics from Metadynamics: Principles, Applications, and Outlook

Ray,

Parrinello

2023

J. Chem. Theory Comput.

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Metadynamics is a popular enhanced sampling algorithm for computing the free energy landscape of rare events by using molecular dynamics simulation. Ten years ago, Tiwary and Parrinello introduced the infrequent metadynamics approach for calculating the kinetics of transitions across free energy barriers. Since then, metadynamics-based methods for obtaining rate constants have attracted significant attention in computational molecular science. Such methods have been applied to study a wide range of problems, including protein−ligand binding, protein folding, conformational transitions, chemical reactions, catalysis, and nucleation. Here, we review the principles of elucidating kinetics from metadynamics-like approaches, subsequent methodological developments in this area, and successful applications on chemical, biological, and material systems. We also highlight the challenges of reconstructing accurate kinetics from enhanced sampling simulations and the scope of future developments.

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“…Blood plasma contains several carrier proteins; however, HSA is the only plasma protein that is capable of reversible binding with a wide diversity of high-affinity ligands and can transport endogenous and exogenous molecules (e.g., fats, hormones, amino acids, drugs, metabolites, and nutrients, metal ions, and other proteins) . Because HSA has a long half-life and low immunogenicity, it has been successfully used to stabilize and improve the efficacy of therapeutics such as interferon (IFN), interleukin-2 (IL-2), antibodies, and vascular endothelial growth factor. − …”

Section: Sasmentioning

confidence: 99%

Insight on Serum Albumin: From Structure and Biological Properties to Functional Biomaterials for Bone Repair

Jin

Hou

2023

ACS Biomater. Sci. Eng.

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Serum albumin (SA), one of the most abundant proteins in blood plasma, plays essential roles in all living processes and has been used in various biomedical applications. Biomaterials fabricated from SAs (human SA, bovine SA, and ovalbumin) exhibit proper microstructure and hydrophilicity as well as remarkable biocompatibility; this makes them ideal for use in bone regeneration. This review provides a comprehensive overview of the structure, physicochemical properties, and biological features of SAs. SAs can be used to generate a wide array of biomaterials for bone repair because of their flexible structure and diverse functions, which enables us to control structure and morphology as well as modulate the biological responses with host tissue. This review summarizes the material categories, forms, and fabrication methods of SA in bone repair. Finally, concerns for future studies in biomedical fields with SA-derived biomaterials are discussed.

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Binding of the B-Raf Inhibitors Dabrafenib and Vemurafenib to Human Serum Albumin: A Biophysical and Molecular Simulation Study

Cited by 6 publications

References 101 publications

Bioactives Promiscuity of Mucin: Insight from Multi-Spectroscopic, Thermodynamic, and Molecular Dynamic Simulation Analyses

Bioactives Promiscuity of Mucin: Insight from Multi-Spectroscopic, Thermodynamic, and Molecular Dynamic Simulation Analyses

Kinetics from Metadynamics: Principles, Applications, and Outlook

Insight on Serum Albumin: From Structure and Biological Properties to Functional Biomaterials for Bone Repair

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