Drug Binding Rates Research Articles

Numerical investigation of the pharmacokinetics and pharmacodynamics of the chemotherapeutic drug in avascular and vascular stages of a brain tumor

One of the most commonly used approaches for treating solid tumors is the systemic delivery of chemotherapeutic drugs. However, our understanding of the factors influencing treatment efficacy through this method is still limited. This study presents a comprehensive and realistic mathematical model that incorporates the dynamics of tumor growth, capillary network extension, and drug delivery in a coupled and simultaneous manner. The model covers two stages of tumor growth: avascular and vascular. For tumor growth, a continuum model is employed using the phase field interface-capturing method. The neo-vascularization process is modeled using a hybrid discrete-continuum approach. Additionally, a multi-scale model is used to describe the pharmacokinetics of doxorubicin, considering various agents. The study investigates the effect of haptotaxis and reveals that a higher haptotaxis coefficient leads to faster tumor growth (up to 2.6 times) and a quicker progression to angiogenesis. The impact of tumor-related and drug-related parameters is also examined, including tumor size, tumor sensitivity to the drug, chemotherapy initialization, treatment cycle duration, drug affinity to cells, and drug dose. The findings indicate that chemotherapy is more effective during the angiogenesis stage when active loops have formed. Other clinical methods such as radiotherapy and surgery may be more appropriate during the avascular stage or the transition period between angiogenesis initialization and loop formation. The penetration depth of the drug decreases by approximately 50% with an increase in the drug binding rate to surface-cell receptors. As a result, high-associate-rate drugs are preferred for chemotherapy after active loops have formed, while low-associate-rate drugs are suitable for earlier stages.

Steady-state and transient effects of SK channel block and adrenergic stimulation to counteract acetylcholine-induced arrhythmogenic effects in the human atria: A computational study

Hyperactivity of the parasympathetic nervous system has been linked to the development of paroxysmal atrial fibrillation (AF). The parasympathetic neurotransmitter acetylcholine (ACh) causes a reduction in action potential (AP) duration (APD) and an increase in resting membrane potential (RMP), both of which contribute to enhance the risk for reentry. Research suggests that small-conductance calcium activated potassium (SK) channels may be an effective target for treating AF. Therapies targeting the autonomic nervous system, either alone or in combination with other drugs, have been explored and have been shown to decrease the incidence of atrial arrhythmias. This study uses computational modeling and simulation to examine the impact of SK channel block (SKb) and β-adrenergic stimulation through Isoproterenol (Iso) on countering the negative effects of cholinergic activity in human atrial cell and 2D tissue models. The steady-state effects of Iso and/or SKb on AP shape, APD at 90% repolarization (APD90) and RMP were evaluated. The ability to terminate stable rotational activity in cholinergically-stimulated 2D tissue models of AF was also investigated. A range of SKb and Iso application kinetics, which reflect varying drug binding rates, were taken into consideration. The results showed that SKb alone prolonged APD90 and was able to stop sustained rotors in the presence of ACh concentrations up to 0.01 μM. Iso terminated rotors under all tested ACh concentrations, but resulted in highly-variable steady-state outcomes depending on baseline AP morphology. Importantly, the combination of SKb and Iso resulted in greater APD90 prolongation and showed promising anti-arrhythmic potential by stopping stable rotors and preventing re-inducibility.

Rate-dependent effects of lidocaine on cardiac dynamics: Development and analysis of a low-dimensional drug-channel interaction model.

State-dependent sodium channel blockers are often prescribed to treat cardiac arrhythmias, but many sodium channel blockers are known to have pro-arrhythmic side effects. While the anti and proarrhythmic potential of a sodium channel blocker is thought to depend on the characteristics of its rate-dependent block, the mechanisms linking these two attributes are unclear. Furthermore, how specific properties of rate-dependent block arise from the binding kinetics of a particular drug is poorly understood. Here, we examine the rate-dependent effects of the sodium channel blocker lidocaine by constructing and analyzing a novel drug-channel interaction model. First, we identify the predominant mode of lidocaine binding in a 24 variable Markov model for lidocaine-sodium channel interaction by Moreno et al. Specifically, we find that (1) the vast majority of lidocaine bound to sodium channels is in the neutral form, i.e., the binding of charged lidocaine to sodium channels is negligible, and (2) neutral lidocaine binds almost exclusively to inactivated channels and, upon binding, immobilizes channels in the inactivated state. We then develop a novel 3-variable lidocaine-sodium channel interaction model that incorporates only the predominant mode of drug binding. Our low-dimensional model replicates an extensive amount of the voltage-clamp data used to parameterize the Moreno et al. model. Furthermore, the effects of lidocaine on action potential upstroke velocity and conduction velocity in our model are similar to those predicted by the Moreno et al. model. By exploiting the low-dimensionality of our model, we derive an algebraic expression for level of rate-dependent block as a function of pacing frequency, restitution properties, diastolic and plateau potentials, and drug binding rate constants. Our model predicts that the level of rate-dependent block is sensitive to alterations in restitution properties and increases in diastolic potential, but it is insensitive to variations in the shape of the action potential waveform and lidocaine binding rates.

Viewing SARS-CoV-2 Nucleocapsid Protein in Terms of Molecular Flexibility.

Simple SummaryNucleocapsid protein is one of the essential proteins for viral replication including the coronavirus SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19) pneumonia leading to the ongoing pandemic. Whereas this protein has emerged as a potential drug target, its physicochemical properties and the molecular mechanism of how this protein is involved in viral replication remain unclear. In this review, structural and dynamical aspects of the SARS-CoV-2 nucleocapsid protein (NCoV2), which should play a key role in a new drug development and in the interaction with RNA and other proteins are summarized. The structural feature of NCoV2 is first described. Next, simulation studies on the interaction between potential drug molecules and NCoV2 are summarized, which show the importance of molecular flexibility. Then, liquid-liquid phase separation phenomenon involving NCoV2, which has recently been reported, is described. This phenomenon also suggests the importance of molecular flexibility of NCoV2. Finally, a promising method using neutron scattering to characterize the structure and structural fluctuation of the droplets, which are formed through this phenomenon, is presented.The latest coronavirus SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19) pneumonia leading to the pandemic, contains 29 proteins. Among them, nucleocapsid protein (NCoV2) is one of the abundant proteins and shows multiple functions including packaging the RNA genome during the infection cycle. It has also emerged as a potential drug target. In this review, the current status of the research of NCoV2 is described in terms of molecular structure and dynamics. NCoV2 consists of two domains, i.e., the N-terminal domain (NTD) and the C-terminal domain (CTD) with a disordered region between them. Recent simulation studies have identified several potential drugs that can bind to NTD or CTD with high affinity. Moreover, it was shown that the degree of flexibility in the disordered region has a large effect on drug binding rate, suggesting the importance of molecular flexibility for the NCoV2 function. Molecular flexibility has also been shown to be integral to the formation of droplets, where NCoV2, RNA and/or other viral proteins gather through liquid-liquid phase separation and considered important for viral replication. Finally, as one of the future research directions, a strategy for obtaining the structural and dynamical information on the proteins contained in droplets is presented.

First application of CE-ICP-MS for monitoring the formation of cisplatin targeting delivery systems with gold nanocarriers.

Cisplatin is a drug frequently used in chemotherapy of various types of tumors due to its strong cytostatic activity against cancer cells. However, this therapy is not free from severe side effects related to the nonselective action of the drug. The solution to this problem could be the application of drug-targeted delivery systems (DTDSs). Gold nanoparticles can be used in such systems as selective drug carriers, ensuring its transportation through the bloodstream to destination tissue. The method of DTDSs analysis providing qualitative and quantitative information about the formation of this conjugation is crucial to establish the kinetics of reaction and stoichiometry of reagents, which ensures the best drug binding rate. Moreover, the status of so far proposed techniques/methods dedicated to elaborating the course of DTDSs formation is preliminary and in majority guarantee only the confirmation of drug-carrier conjugate formation. In this paper, we demonstrate the procedures of reagents' preparation and cisplatin-gold nanoparticles DTDS formation, which have a significant influence on the rate and stoichiometry of the reaction. We also present the novel application of CE-ICP-MS hyphenation for effective separation and online monitoring of all components of the reaction mixture.

Spectroscopic and molecular docking studies of the interaction between meloxicam and pepsin

In order to study the interaction mechanism between meloxicam and pepsin, the interaction between meloxicam and pepsin was studied by fluorescence spectroscopy, UV-visible absorption spectroscopy, circular dichroism spectroscopy and molecular docking under physiological conditions (pH = 2.20). The results of spectral experiments showed that meloxicam quenched the intrinsic fluorescence of pepsin by static quenching, formed a stable complex at 1:1, and changed the conformation of pepsin. The thermodynamic results showed that the main force type of meloxicam and pepsin system was hydrophobic interaction. Molecular docking showed that there was a hydrogen bond in addition to hydrophobic interaction, and the best binding site between meloxicam and pepsin was near the catalytic active center of pepsin. The results showed that the combination of the meloxicam and pepsin changed the microenvironment of amino acid residues at the catalytic active center of pepsin. Under the experimental conditions, the protein binding rate of meloxicam to pepsin W(B) was 2.97–48.3%, indicating that the binding of meloxicam to pepsin had an effect on the number of free pepsin. The drug binding rate of the system W(Q) was 2.97–1.39%, indicating that the binding effect of meloxicam and pepsin on the number of free drug molecules was weak, so the binding effect would not have a significant effect on the efficacy of meloxicam.

Spectroscopic study on the mechanism of meloxicam and α-amylase

In order to explore the mechanism of action of meloxicam and α-amylase. The interaction between the rheumatoid arthritis drug meloxicam and α-amylase was studied by fluorescence spectroscopy, synchronous fluorescence spectroscopy and molecular docking under the experimental conditions of pH=6.80. The results showed that meloxicam was able to effectively quench the endogenous fluorescence of α-amylase in a static quenching form a 1:1 complex and change the conformation of α-amylase. Thermodynamic results indicated that the main type of meloxicam and α-amylase system was hydrophobic interaction. Molecular docking indicated that the binding system had hydrogen bonds in addition to hydrophobic interaction and meloxicam was surrounded by the active amino acid residues Trp13 and Trp263 of α-amylase, which changed the microenvironment of amino acid residues at the active center of α-amylase. By establishing the binding model, it can be seen that the protein binding rate W(B) of meloxicam to α-amylase was 2.76%-41.79% under the experimental conditions. The results showed that the binding of meloxicam to α-amylase had an effect on the number of free α-amylase. The drug binding rate W(Q) of the system was 2.76%-1.67%, which indicated that the combination of α-amylase and meloxicam would not affect the efficacy of meloxicam.

Spectroscopic and Molecular Docking Investigations on the Effect of the Interaction Between Cefoperazone Sodium and Papain to Drug Efficacy

Under the experimental condition of pH=7.40, papain (PAPA) was used as the detection object, and the binding behavior of cefoperazone sodium (CFZ) and PAPA at three temperatures was studied by multi-spectroscopy and molecular docking. The results showed that CFZ can effectively quench the endogenous fluorescence of PAPA, form a 1:1 complex, and change the conformation of PAPA. At 293 K, the fluorescence intensity of the system had a good linear relationship with the CFZ concentration in the range of 4.0×10-6 ∼ 1.0×10-4 mol/L. The detection limit of the method was 2.43×10-6 mol/L (n=10), indicating that the reaction can be used to achieve rapid determination of CFZ content in the actual drug. Based on the experimental data, a mathematical model combining CFZ and PAPA was established. When the peak plasma concentration of CFZ was 106.0 mg/L after intravenous infusion of 1 g, the drug binding rate of CFZ-PAPA system was 2.70 %, indicating the combination of CFZ and PAPA did not affect the efficacy of CFZ, that is, when taking CFZ, it is safe to consume PAPA. Molecular simulation studies had showed that the interaction between CFZ and PAPA had not only electrostatic forces but also hydrogen bonding, which was consistent with the results of spectroscopy and thermodynamic studies.

Acid-sensitive dextran prodrug: A higher molecular weight makes a better efficacy

The acid-sensitive polymer prodrugs have attracted increasing attention because of their selective intratumoral or intracellular drug release. Herein, two intracellular acid-sensitive dextran−doxorubicin (Dex−DOX) conjugates with similar drug binding rate were synthesized through the Schiff base reaction between the aldehyde group in the oxidized Dex with different lengths and the amino group of DOX. The amphiphilic Dex−DOX conjugates self-assembled into micellar nanoparticles in phosphate-buffered saline (PBS). The micelle of prodrug with longer Dex, that is, Dex500k-DOX, exhibited smaller size, quicker drug release, higher cell internalization, and stronger tumor suppression with upregulated security in comparison with the one with shorter Dex, that is, Dex40k-DOX. Therefore, the molecular weight of prodrug backbone could adjust the properties, and a higher molecular weight endowed the Dex−DOX conjugate with a better antitumor efficacy in a limited number of tested samples.

A temperature-dependent in silico model of the human ether-à-go-go-related (hERG) gene channel

IntroductionCurrent regulatory guidelines for assessing the risk of QT prolongation include in vitro assays assessing drug effects on the human ether-à-go-go-related (hERG; also known as Kv11.1) channel expressed in cell lines. These assays are typically conducted at room temperature to promote the ease and stability of recording hERG currents. However, the new Comprehensive in vitro Proarrhythmia Assay (CiPA) paradigm proposes to use an in silico model of the human ventricular myocyte to assess risk, requiring as input hERG channel pharmacology data obtained at physiological temperatures. To accommodate current industry safety pharmacology practices for measuring hERG channel activity, an in silico model of hERG channel that allows for the extrapolation of hERG assay data across different temperatures is desired. Because temperature may have an effect on both channel gating and drug binding rate, such models may need to have two components: a base model dealing with temperature-dependent gating changes without drug, and a pharmacodynamic component simulating temperature-dependent drug binding kinetics. As a first step, a base mode that can capture temperature effects on hERG channel gating without drug is needed. Methods and resultsTo meet this need for a temperature-dependent base model, a Markov model of the hERG channel with state transition rates explicitly dependent on temperature was developed and calibrated using data from a variety of published experiments conducted over a range of temperatures. The model was able to reproduce observed temperature-dependent changes in key channel gating properties and also to predict the results obtained in independent sets of new experiments. DiscussionThis new temperature-sensitive model of hERG gating represents an attempt to improve the predictivity of safety pharmacology testing by enabling the translation of room temperature hERG assay data to more physiological conditions. With further development, this model can be incorporated into the CiPA paradigm and also be used as a tool for developing insights into the thermodynamics of hERG channel gating mechanisms and the temperature-dependence of hERG channel block by drugs.

Drug binding rate regulates the properties of polysaccharide prodrugs

Three intracellular acid-degradable hydroxyethyl starch-doxorubicin (HES[double bond, length as m-dash]DOX) prodrugs with different drug binding rates (DBRs) were synthesized through the conjugation of oxidized HES and DOX with a pH-responsive Schiff base bond. The DBRs of HES[double bond, length as m-dash]DOX conjugates were determined to be 1.7, 3.3, and 5.9%, which could be facilely adjusted by the feeding molar amount of DOX. All HES[double bond, length as m-dash]DOX conjugates could spontaneously self-assemble into spherical micellar nanoparticles in phosphate-buffered saline. The hydrodynamic diameter decreased from 73.4 ± 5.3, 63.9 ± 5.5, to 51.9 ± 8.5 nm with the increase of the DBR from 1.7, 3.3, to 5.9%. The DOX release from HES[double bond, length as m-dash]DOX could be accelerated by the decrease of pH and the DBR, attributed to the acid-sensitive Schiff base bond and the loose core, respectively. Furthermore, the HES[double bond, length as m-dash]DOX micelle selectively released DOX in the endosome and/or lysosome after cellular uptake, and exhibited excellent proliferation inhibition toward murine melanoma B16F10 cells in vitro and in vivo. Furthermore, the antitumor efficacy was upregulated by the increase of the DBR, benefiting from the selective acidity-triggered DOX release in tumor cells. These results indicated that HES[double bond, length as m-dash]DOX exhibited great potential in the precise chemotherapy of malignancy.

Inhibition of Na(+) current by imipramine and related compounds: different binding kinetics as an inactivation stabilizer and as an open channel blocker.

Use-dependent block of Na(+) channels plays an important role in the action of many medications, including the anticonvulsants phenytoin, carbamazepine, and lamotrigine. These anticonvulsants all slowly yet selectively bind to a common receptor site in inactivated but not resting Na(+) channels, constituting the molecular basis of the use-dependent block. However, it remains unclear what channel gating process "makes" the receptor, where the receptor is located, and how the slow drug binding rate (to the inactivated channels) is contrived. Imipramine has a diphenyl structural motif almost identical to that in carbamazepine (a dibenzazepine tricyclic compound), as well as a tertiary amine chain similar to that in many prototypical local anesthetics, and has also been reported to inhibit Na(+) channels in a use-dependent fashion. We found that imipramine selectively binds to the inactivated (dissociation constant approximately 1.3 microM) rather than the resting Na(+) channels (dissociation constant >130 microM). Moreover, imipramine rapidly blocks open Na(+) channels, with a binding rate approximately 70-fold faster than its binding to the inactivated channels. Similarly, carbamazepine and diphenhydramine are open Na(+) channel blockers with faster binding rates to the open than to the inactivated channels. These findings indicate that the anticonvulsant receptor responsible for the use-dependent block of Na(+) channels is located in or near the pore (most likely in the pore mouth) and is made suitable for drug binding during channel activation. The receptor, however, continually changes its conformation in the subsequent gating process, causing the slower drug binding rates to the inactivated Na(+) channels.