Inertial effects and diffusion

McGahay, V.

doi:10.1016/j.jnoncrysol.2004.08.148

Cited by 12 publications

(7 citation statements)

References 39 publications

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“…The residency of the encounter complex increases the possibility of mutual perturbation of the ligand and the receptor conformational landscape, which may lead to a reduction of the barrier height. This is consistent with the observation that the forward rate constant k on is diffusion-limited in a large number of biological processes. − …”

Section: Introductionsupporting

confidence: 90%

Characterization of the Ligand Receptor Encounter Complex and Its Potential for in Silico Kinetics-Based Drug Development

Twarock¹,

Lane

Verma

et al. 2011

J. Chem. Theory Comput.

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The study of drug-receptor interactions has largely been framed in terms of the equilibrium thermodynamic binding affinity, an in vitro measure of the stability of the drug-receptor complex that is commonly used as a proxy measure of in vivo biological activity. In response to the growing realization of the importance of binding kinetics to in vivo drug activity we present a computational methodology for the kinetic characterization of drug-receptor interactions in terms of the encounter complex. Using trajectory data from multiple Brownian dynamics simulations of ligand diffusion, we derive the spatial density of the ligand around the receptor and show how it can be quantitatively partitioned into different basins of attraction. Numerical integration of the ligand densities within the basins can be used to estimate the residence time of the ligand within these diffusive binding sites. Simulations of two structurally similar inhibitors of Hsp90 exhibit diffusive binding sites with similar spatial structure but with different ligand residence times. In contrast, a pair of structurally dissimilar inhibitors of MDM2, a peptide and a small molecule, exhibit spatially distinct basins of attraction around the receptor, which in turn reveal differences in ligand orientational order. Thus, our kinetic approach provides microscopic details of drug-receptor dynamics that provide novel insight into the observed differences in the thermodynamic binding affinities for the two inhibitors, such as the differences in the entropic contributions to binding. The characterization of the encounter complex, in terms of the structure, topology, and dynamics of diffusive binding sites, offers a new perspective on ligand-receptor interactions and the potential for greater insight into drug action. The method, which requires no prior knowledge of the bound state, is a first step toward the incorporation of ligand kinetics into in silico drug development protocols.

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Section: Introductionsupporting

confidence: 90%

Characterization of the Ligand Receptor Encounter Complex and Its Potential for in Silico Kinetics-Based Drug Development

Twarock¹,

Lane

Verma

et al. 2011

J. Chem. Theory Comput.

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“…However, the final DO concentrations of the chamber were stable at 1.4 and 1.6% when the flow rates of the liquid were 30 and 40 μL/min, respectively. All the above results indicated that the liquid flow rate was too fast to diffuse sufficiently between the gas and liquid when the flow rate was ≥30 μL/min, resulting in the DO concentration of the cell chamber being higher than that of the gas being pumped in . We inferred that the most appropriate liquid flow rate was 20 μL/min.…”

Section: Resultsmentioning

confidence: 89%

“…All the above results indicated that the liquid flow rate was too fast to diffuse sufficiently between the gas and liquid when the flow rate was ≥30 μL/min, resulting in the DO concentration of the cell chamber being higher than that of the gas being pumped in. 19 We inferred that the most appropriate liquid flow rate was 20 μL/min. Therefore, the system was operated with a flow rate of 20 μL/min during the first 2 h and then changed to 1 μL/min for long-term cell culturing to avoid the shear stress damaging the cells.…”

Section: ■ Results and Discussionmentioning

confidence: 98%

An Oxygen-Concentration-Controllable Multiorgan Microfluidic Platform for Studying Hypoxia-Induced Lung Cancer-Liver Metastasis and Screening Drugs

et al. 2021

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Various cancer metastasis models based on organ-on-a-chip platforms have been established to study molecular mechanisms and screen drugs. However, current platforms can neither reveal hypoxia-induced cancer metastasis mechanisms nor allow drug screening under a hypoxia environment on a multiorgan level. We have developed a three-dimensional-culture multiorgan microfluidic (3D-CMOM) platform in which the dissolved oxygen concentration can be precisely controlled. An organ-level lung cancer and liver linkage model was established under normoxic/hypoxic conditions. A transcriptomics analysis of the hypoxia-induced lung cancer cells (A549 cells) on the platform indicated that the hypoxia-inducible factor 1α (HIF-1α) pathway could elevate epithelial-mesenchymal transition (EMT) transcription factors (Snail 1 and Snail 2), which could promote cancer metastasis. Then, protein detection demonstrated that HIF-1α and EMT transcription factor expression levels were positively correlated with the secretion of cancer metastasis damage factors alphafetoprotein (AFP), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (γ-GT) from liver cells. Furthermore, the cancer treatment effects of HIF-1α inhibitors (tirapazamine, SYP-5, and IDF-11774) were evaluated using the platform. The treatment effect of SYP-5 was enhanced under the hypoxic conditions with fewer side effects, similar to the findings of TPZ. We can envision its wide application in future investigations of cancer metastasis and screening of drugs under hypoxic conditions with the potential to replace animal experiments.

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“…It should be observed that overshot dynamics in sorption experiments have been observed in transport across polymeric matrices where the viscoelastic response of the material is responsible for the occurrence of memory effect in mass transport (see [24] and reference therein, and particularly figure 1 in this article based on closed-form solution of the transmission-line equation [25]). However, while in sorption experiments an overshot in the overall sorption curve does not violate in principle any fundamental law…”

Section: The Cattaneo Equation On the Unit Intervalmentioning

confidence: 99%

One-dimensional hyperbolic transport: Positivity and admissible boundary conditions derived from the wave formulation

Brasiello¹,

Crescitelli²,

Giona³

2016

Physica A: Statistical Mechanics and its Applications

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We consider the one-dimensional Cattaneo equation for transport of scalar fields such as solute concentration and temperature in mass and heat transport problems, respectively. Although the Cattaneo equation admits a stochastic interpretation -at least in the one-dimensional case -negative concentration values can occur in boundary-value problems on a finite interval. This phenomenon stems from the probabilistic nature of this model: the stochastic interpretation provides constraints on the admissible boundary conditions, as can be deduced from the wave formulation here presented. Moreover, as here shown, energetic inequalities and the dissipative nature of the equation provide an alternative way to derive the same constraints on the boundary conditions derived by enforcing positivity. The analysis reported is also extended to transport problems in the presence of a biasing velocity field. Several general conclusions are drawn from this analysis that could be extended to the higher-dimensional case.

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Inertial effects and diffusion

Cited by 12 publications

References 39 publications

Characterization of the Ligand Receptor Encounter Complex and Its Potential for in Silico Kinetics-Based Drug Development

Characterization of the Ligand Receptor Encounter Complex and Its Potential for in Silico Kinetics-Based Drug Development

An Oxygen-Concentration-Controllable Multiorgan Microfluidic Platform for Studying Hypoxia-Induced Lung Cancer-Liver Metastasis and Screening Drugs

One-dimensional hyperbolic transport: Positivity and admissible boundary conditions derived from the wave formulation

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