scholarly journals A quantitative mechanistic PK/PD model directly connects Btk target engagement and in vivo efficacy

2017 ◽  
Vol 8 (5) ◽  
pp. 3434-3443 ◽  
Author(s):  
Fereidoon Daryaee ◽  
Zhuo Zhang ◽  
Kayla R. Gogarty ◽  
Yong Li ◽  
Jonathan Merino ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Target Engagement ◽  
In Vivo Efficacy ◽  
Drug Activity

Correlating target engagement with in vivo drug activity remains a central challenge in efforts to improve the efficiency of drug discovery.

scholarly journals Predictability of Peripheral Lymphocyte Reduction of Novel S1P1 Agonists by In Vitro GPCR Signaling Profile

2013 ◽  
Vol 18 (9) ◽  
pp. 997-1007 ◽  
Author(s):  
Han Xu ◽  
Michele McElvain ◽  
Mike Fiorino ◽  
Brad Henkle ◽  
Lisa Sherman ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Adenylyl Cyclase ◽  
Peripheral Lymphocyte ◽  
Receptor Internalization ◽  
In Vitro Assays ◽  
Vitro Assay ◽  
In Vivo Efficacy ◽  
Erk Phosphorylation

Surrogate readouts of G-protein–coupled receptor signaling pathways using highly engineered systems are often employed in the drug discovery process. However, accumulating data have demonstrated the importance of selecting relevant biological activity rather than technically facile assays to support high-throughout screening and subsequent structure-activity relationship studies. Here we report a case study using sphingosine-1-phosphate receptor 1 (S1P1) as the model system to compare compound activity in six different in vitro assays with their ability to predict in vivo efficacy. S1P1 has long been validated as a therapeutic target for autoimmune diseases. In this article, in vivo and in vitro studies on 19 S1P1 agonists are reported. In vitro activities of these S1P1 agonists, together with S1P and FTY720p, on Ca2+ mobilization, adenylyl cyclase inhibition, extracellular signal-related kinase (ERK) phosphorylation, β-arrestin recruitment, and receptor internalization, were determined. The in vitro potency of these compounds was correlated with their ability to induce peripheral lymphocyte reduction. The results revealed that inhibition of adenylyl cyclase and induction of β-arrestin recruitment and receptor internalization are good indicators to predict in vivo efficacy, whereas induction of Ca2+ mobilization through Gqi/5 coupling and ERK phosphorylation is irrelevant. This study demonstrated the importance of identifying an appropriate in vitro assay to predict in vivo activity based on the biological relevance in the drug discovery setting.

scholarly journals A kinetic operational model of agonism incorporating receptor desensitization for G-protein-coupled receptors

2019 ◽  
Author(s):  
Sam R.J. Hoare ◽  
David A. Hall ◽  
Lloyd J. Bridge
Keyword(s):  
Drug Discovery ◽  
Time Course ◽  
Drug Effect ◽  
Model Parameters ◽  
List Type ◽  
Receptor Desensitization ◽  
Short Term ◽  
In Vivo Efficacy ◽  
Regulation Mechanisms

AbstractPharmacological responses are modulated over time by regulation of signaling mechanisms. The canonical short-term regulation mechanisms are receptor desensitization and degradation of the response. Here for the first time a pharmacological model for measuring drug parameters is developed that incorporates short-term mechanisms of regulation of signaling. The model is formulated in a manner that enables measurement of drug parameters using familiar curve fitting methods. The efficacy parameter is kτ, which is simply the initial rate of signaling before it becomes limited by regulation mechanisms. The regulation parameters are rate constants, kDES for receptor desensitization and kD for response degradation. Efficacy and regulation are separate parameters, meaning these properties can be optimized independently of one another in drug discovery. The parameters can be applied to translate in vitro findings to in vivo efficacy in terms of the magnitude and duration of drug effect. When the time course data conform to certain shapes, for example the association exponential curve, a mechanism-agnostic approach can be applied to estimate agonist efficacy, without the need to know the underlying regulatory mechanisms. The model was verified by comparison with historical data and by fitting these data to estimate the model parameters. This new model for quantifying drug activity can be broadly applied to the short-term cell signaling assays used routinely in drug discovery and to aid their translation to in vivo efficacy, facilitating the development of new therapeutics.HighlightsRegulation of signaling impacts measurement of drug effectReceptor desensitization is incorporated here into a kinetic model of signalingDrug effect and signaling regulation can now be measured independentlyThe analysis framework is designed for signaling assays used in drug discoveryThese new analysis capabilities will aid development of new therapeutics

Quantitative Ranking of Ligand Binding Kinetics with a Multiscale Milestoning Simulation Approach

2018 ◽  
Author(s):  
Benjamin R. Jagger ◽  
Christoper T. Lee ◽  
Rommie Amaro
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Small Molecule ◽  
Brownian Dynamics ◽  
Model Simulation ◽  
Computational Cost ◽  
Lead Selection ◽  
Delta G ◽  
Dynamics Simulations

<p>The ranking of small molecule binders by their kinetic (kon and koff) and thermodynamic (delta G) properties can be a valuable metric for lead selection and optimization in a drug discovery campaign, as these quantities are often indicators of in vivo efficacy. Efficient and accurate predictions of these quantities can aid the in drug discovery effort, acting as a screening step. We have previously described a hybrid molecular dynamics, Brownian dynamics, and milestoning model, Simulation Enabled Estimation of Kinetic Rates (SEEKR), that can predict kon’s, koff’s, and G’s. Here we demonstrate the effectiveness of this approach for ranking a series of seven small molecule compounds for the model system, -cyclodextrin, based on predicted kon’s and koff’s. We compare our results using SEEKR to experimentally determined rates as well as rates calculated using long-timescale molecular dynamics simulations and show that SEEKR can effectively rank the compounds by koff and G with reduced computational cost. We also provide a discussion of convergence properties and sensitivities of calculations with SEEKR to establish “best practices” for its future use.</p>

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

Sign in / Sign up

Export Citation Format

Share Document