scholarly journals Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients

2015 ◽  
Vol 11 (1) ◽  
pp. 45-63 ◽  
Author(s):  
Wilhelmus EA de Witte ◽  
Yin Cheong Wong ◽  
Indira Nederpelt ◽  
Laura H Heitman ◽  
Meindert Danhof ◽  
...  
Keyword(s):  
Drug Target ◽  
Drug Effects ◽  
Binding Kinetics ◽  
Mechanistic Models ◽  
Rational Use ◽  
Target Binding

scholarly journals Multi-scale modeling of drug binding kinetics to predict drug efficacy

2019 ◽  
Vol 77 (3) ◽  
pp. 381-394 ◽  
Author(s):  
Fabrizio Clarelli ◽  
Jingyi Liang ◽  
Antal Martinecz ◽  
Ines Heiland ◽  
Pia Abel zur Wiesch
Keyword(s):  
Mathematical Models ◽  
Drug Efficacy ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Multi Scale ◽  
Drug Concentrations ◽  
Body Compartments ◽  
Target Binding

AbstractOptimizing drug therapies for any disease requires a solid understanding of pharmacokinetics (the drug concentration at a given time point in different body compartments) and pharmacodynamics (the effect a drug has at a given concentration). Mathematical models are frequently used to infer drug concentrations over time based on infrequent sampling and/or in inaccessible body compartments. Models are also used to translate drug action from in vitro to in vivo conditions or from animal models to human patients. Recently, mathematical models that incorporate drug-target binding and subsequent downstream responses have been shown to advance our understanding and increase predictive power of drug efficacy predictions. We here discuss current approaches of modeling drug binding kinetics that aim at improving model-based drug development in the future. This in turn might aid in reducing the large number of failed clinical trials.

scholarly journals In vitro and in silico analysis of the effects of D2 receptor antagonist target binding kinetics on the cellular response to fluctuating dopamine concentrations

2018 ◽  
Vol 175 (21) ◽  
pp. 4121-4136 ◽  
Author(s):  
Wilhelmus E A de Witte ◽  
Joost W Versfelt ◽  
Maria Kuzikov ◽  
Solene Rolland ◽  
Victoria Georgi ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
In Silico ◽  
Cellular Response ◽  
D2 Receptor ◽  
In Silico Analysis ◽  
Binding Kinetics ◽  
Target Binding ◽  
Silico Analysis

scholarly journals Detecting Drug-Target Binding in Cells using Fluorescence Activated Cell Sorting Coupled with Mass Spectrometry Analysis

2017 ◽  
Author(s):  
Kris Wilson ◽  
Scott P Webster ◽  
John P Iredale ◽  
Xiaozhong Zheng ◽  
Natalie Z Homer ◽  
...  
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Mass Spectrometry Analysis ◽  
Protein Targets ◽  
Target Proteins ◽  
Spectrometry Analysis ◽  
Cellular Permeability ◽  
Target Binding ◽  
Hit Validation

AbstractThe assessment of drug-target engagement for determining the efficacy of a compound inside cells remains challenging, particularly for difficult target proteins. Existing techniques are more suited to soluble protein targets. Difficult target proteins include those with challenging in vitro solubility, stability or purification properties that preclude target isolation. Here, we report a novel technique that measures intracellular compound-target complex formation, as well as cellular permeability, specificity and cytotoxicity - the Toxicity-Affinity-Permeability-Selectivity (TAPS) technique. The TAPS assay is exemplified here using human kynurenine 3-monooxygenase (KMO), a challenging intracellular membrane protein target of significant current interest. TAPS confirmed target binding of known KMO inhibitors inside cells. We conclude that the TAPS assay can be used to facilitate intracellular hit validation on most, if not all intracellular drug targets.

scholarly journals Molecular Interaction Characterization Strategies for the Development of New Biotherapeutic Antibody Modalities

Antibodies ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 7
Author(s):  
Xiangdan Wang ◽  
Minh Michael Phan ◽  
Ji Li ◽  
Herman Gill ◽  
Simon Williams ◽  
...  
Keyword(s):  
Molecular Interaction ◽  
Binding Kinetics ◽  
Therapeutic Development ◽  
Dosing Regimens ◽  
Fit For Purpose ◽  
Target Binding ◽  
The Impact ◽  
First Time

The characterization of target binding interactions is critical at each stage of antibody therapeutic development. During early development, it is important to design fit-for-purpose in vitro molecular interaction characterization (MIC) assays that accurately determine the binding kinetics and the affinity of therapeutic antibodies for their targets. Such information enables PK/PD (pharmacokinetics/pharmacodynamics) modeling, estimation of dosing regimens, and assessment of potency. While binding kinetics and affinities seem to be readily obtained, there is little discussion in the literature on how the information should be generated and used in a systematic manner along with other approaches to enable key drug development decisions. The introduction of new antibody modalities poses unique challenges to the development of MIC assays and further increases the need to discuss the impact of developing context-appropriate MIC assays to enable key decision making for these programs. In this paper, we discuss for the first time the challenges encountered when developing MIC assays supporting new antibody modalities. Additionally, through the presentation of several real case studies, we provide strategies to overcome these challenges to enable investigational new drug (IND) filings.

The Effect of Dipyridamole and RA 233 on Human Platelet Function in Vitro

1973 ◽  
Vol 29 (03) ◽  
pp. 694-700 ◽  
Author(s):  
Paul L. Rifkin ◽  
Marjorie B. Zucker
Keyword(s):  
Mechanism Of Action ◽  
Human Blood ◽  
Glass Bead ◽  
Heart Valves ◽  
Human Platelet ◽  
Drug Effects ◽  
Simple Relation ◽  
Prosthetic Heart Valves ◽  
Induced Aggregation

SummaryDipyridamole (Persantin) is reported to prolong platelet survival and inhibit embolism in patients with prosthetic heart valves, but its mechanism of action is unknown. Fifty jxM dipyridamole failed to reduce the high percentage of platelets retained when heparinized human blood was passed through a glass bead column, but prolonged the inhibition of retention caused by disturbing blood in vitro. Possibly the prostheses act like disturbance. Although RA 233 was as effective as dipyridamole in inhibiting the return of retention, it was less effective in preventing the uptake of adenosine into erythrocytes, and more active in inhibiting ADP-induced aggregation and release. Thus there is no simple relation between these drug effects.

Are Carbonic Anhydrases Suitable Targets to Fight Protozoan Parasitic Diseases?

2019 ◽  
Vol 25 (39) ◽  
pp. 5266-5278 ◽  
Author(s):  
Katia D'Ambrosio ◽  
Claudiu T. Supuran ◽  
Giuseppina De Simone
Keyword(s):  
Drug Resistance ◽  
Animal Models ◽  
Carbonic Anhydrase ◽  
Drug Target ◽  
Treatment Options ◽  
Parasitic Diseases ◽  
Carbonic Anhydrases ◽  
Extensive Drug Resistance ◽  
Protozoan Infections

Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome of these protozoa, with the aim to search for a new drug target for fighting malaria, leishmaniasis and Chagas disease. P. falciparum encodes for a CA (PfCA) belonging to a novel genetic family, the η-CA class, L. donovani chagasi for a β-CA (LdcCA), whereas T. cruzi genome contains an α-CA (TcCA). These three enzymes were characterized in detail and a number of in vitro potent and selective inhibitors belonging to the sulfonamide, thiol, dithiocarbamate and hydroxamate classes were discovered. Some of these inhibitors were also effective in cell cultures and animal models of protozoan infections, making them of considerable interest for the development of new antiprotozoan drugs with a novel mechanism of action.

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