The Experts below are selected from a list of 238830 Experts worldwide ranked by ideXlab platform
Tomas Akerud - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and the Drug-Target residence time concept.
Drug discovery today, 2013Co-Authors: Göran Dahl, Tomas AkerudAbstract:The concept of Drug-Target residence time has been in focus in recent Drug discovery literature. However, few studies consider the combined effect of pharmacokinetics (PK) and binding kinetics (BK) on the duration of effect of a Drug. Using a simple model that takes both PK and BK into account, we found that prolongation of binding owing to a long Drug-Target residence time can only occur when the binding dissociation is slower than the PK elimination. Data for several Drugs and/or Drug candidates in the literature indicate that the opposite is observed, that is, they have a slower elimination compared with dissociation. These observations greatly reduce the usability of Drug-Target residence times for estimating the duration of effect of a Drug in vivo.
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Pharmacokinetics and the Drug–Target residence time concept
Drug Discovery Today, 2013Co-Authors: Göran Dahl, Tomas AkerudAbstract:The concept of Drug-Target residence time has been in focus in recent Drug discovery literature. However, few studies consider the combined effect of pharmacokinetics (PK) and binding kinetics (BK) on the duration of effect of a Drug. Using a simple model that takes both PK and BK into account, we found that prolongation of binding owing to a long Drug-Target residence time can only occur when the binding dissociation is slower than the PK elimination. Data for several Drugs and/or Drug candidates in the literature indicate that the opposite is observed, that is, they have a slower elimination compared with dissociation. These observations greatly reduce the usability of Drug-Target residence times for estimating the duration of effect of a Drug in vivo.
Peter J. Tonge - One of the best experts on this subject based on the ideXlab platform.
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Structure-kinetic relationships that control the residence time of Drug-Target complexes: insights from molecular structure and dynamics.
Current Opinion in Chemical Biology, 2018Co-Authors: James N. Iuliano, Peter J. TongeAbstract:Time-dependent Target occupancy is a function of both the thermodynamics and kinetics of Drug–Target interactions. However, while the optimization of thermodynamic affinity through approaches such as structure-based Drug design is now relatively straight forward, less is understood about the molecular interactions that control the kinetics of Drug complex formation and breakdown since this depends on both the ground and transition state energies on the binding reaction coordinate. In this opinion we highlight several recent examples that shed light on current approaches that are elucidating the factors that control the life-time of the Drug–Target complex.
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rational optimization of Drug Target residence time insights from inhibitor binding to the s aureus fabi enzyme product complex
Biochemistry, 2013Co-Authors: Andrew Chang, J Schiebel, Weixuan Yu, Gopal R Bommineni, Michael V Baxter, Avinash Khanna, Christoph A Sotriffer, Caroline Kisker, Peter J. TongeAbstract:Drug-Target kinetics has recently emerged as an especially important facet of the Drug discovery process. In particular, prolonged Drug-Target residence times may confer enhanced efficacy and selectivity in the open in vivo system. However, the lack of accurate kinetic and structural data for a series of congeneric compounds hinders the rational design of inhibitors with decreased off-rates. Therefore, we chose the Staphylococcus aureus enoyl-ACP reductase (saFabI) — an important Target for the development of new anti-staphylococcal Drugs — as a model system to rationalize and optimize the Drug-Target residence time on a structural basis. Using our new, efficient, and widely applicable mechanistically informed kinetic approach, we obtained a full characterization of saFabI inhibition by a series of 20 diphenyl ethers complemented by a collection of 9 saFabI–inhibitor crystal structures. We identified a strong correlation between the affinities of the investigated saFabI diphenyl ether inhibitors and their...
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Drug Target residence time critical information for lead optimization
Current Opinion in Chemical Biology, 2010Co-Authors: Peter J. TongeAbstract:Failure due to poor in vivo efficacy is a primary contributor to attrition during the development of new chemotherapeutics. Lead optimization programs that in their quest for efficacy focus solely on improving the affinity of Drug-Target binding are flawed, since this approach ignores the fluctuations in Drug concentration that occur in vivo. Instead the lifetime of the Drug-Target complex must also be considered, since Drugs only act when they are bound to their Targets. Consequently, to improve the correlation between the in vitro and in vivo activity of Drugs, measurements of Drug-Target residence time must be incorporated into the Drug discovery process.
Göran Dahl - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics and the Drug-Target residence time concept.
Drug discovery today, 2013Co-Authors: Göran Dahl, Tomas AkerudAbstract:The concept of Drug-Target residence time has been in focus in recent Drug discovery literature. However, few studies consider the combined effect of pharmacokinetics (PK) and binding kinetics (BK) on the duration of effect of a Drug. Using a simple model that takes both PK and BK into account, we found that prolongation of binding owing to a long Drug-Target residence time can only occur when the binding dissociation is slower than the PK elimination. Data for several Drugs and/or Drug candidates in the literature indicate that the opposite is observed, that is, they have a slower elimination compared with dissociation. These observations greatly reduce the usability of Drug-Target residence times for estimating the duration of effect of a Drug in vivo.
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Pharmacokinetics and the Drug–Target residence time concept
Drug Discovery Today, 2013Co-Authors: Göran Dahl, Tomas AkerudAbstract:The concept of Drug-Target residence time has been in focus in recent Drug discovery literature. However, few studies consider the combined effect of pharmacokinetics (PK) and binding kinetics (BK) on the duration of effect of a Drug. Using a simple model that takes both PK and BK into account, we found that prolongation of binding owing to a long Drug-Target residence time can only occur when the binding dissociation is slower than the PK elimination. Data for several Drugs and/or Drug candidates in the literature indicate that the opposite is observed, that is, they have a slower elimination compared with dissociation. These observations greatly reduce the usability of Drug-Target residence times for estimating the duration of effect of a Drug in vivo.
Robert A Copeland - One of the best experts on this subject based on the ideXlab platform.
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The Drug-Target residence time model: A 10-year retrospective
Nature Reviews Drug Discovery, 2016Co-Authors: Robert A CopelandAbstract:The Drug-Target residence time model was first introduced in 2006 and has been broadly adopted across the chemical biology, biotechnology and pharmaceutical communities. While traditional in vitro methods view Drug-Target interactions exclusively in terms of equilibrium affinity, the residence time model takes into account the conformational dynamics of Target macromolecules that affect Drug binding and dissociation. The key tenet of this model is that the lifetime (or residence time) of the binary Drug-Target complex, and not the binding affinity per se, dictates much of the in vivo pharmacological activity. Here, this model is revisited and key applications of it over the past 10 years are highlighted.
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Conformational adaptation in Drug–Target interactions and residence time
Future medicinal chemistry, 2011Co-Authors: Robert A CopelandAbstract:Although Drug–Target interactions are commonly illustrated in terms of structurally static binding and dissociation events, such descriptions are inadequate to explain the impact of conformational dynamics on these processes. For high-affinity interactions, both the association and dissociation of Drug molecules to and from their Targets are often controlled by conformational changes of the Target. Conformational adaptation can greatly influence the residence time of a Drug on its Target (i.e., the lifetime of the binary Drug–Target complex); long residence time can lead to sustained pharmacology and may also mitigate off-Target toxicity. In this perspective, the kinetics of Drug–Target association and dissociation reactions are explored, with particular emphasis on the impact of conformational adaptation on Drug–Target residence time.
Martin Ester - One of the best experts on this subject based on the ideXlab platform.
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simboost a read across approach for predicting Drug Target binding affinities using gradient boosting machines
Journal of Cheminformatics, 2017Co-Authors: Tong He, Marten Heidemeyer, Artem Cherkasov, Martin EsterAbstract:Computational prediction of the interaction between Drugs and Targets is a standing challenge in the field of Drug discovery. A number of rather accurate predictions were reported for various binary Drug–Target benchmark datasets. However, a notable drawback of a binary representation of interaction data is that missing endpoints for non-interacting Drug–Target pairs are not differentiated from inactive cases, and that predicted levels of activity depend on pre-defined binarization thresholds. In this paper, we present a method called SimBoost that predicts continuous (non-binary) values of binding affinities of compounds and proteins and thus incorporates the whole interaction spectrum from true negative to true positive interactions. Additionally, we propose a version of the method called SimBoostQuant which computes a prediction interval in order to assess the confidence of the predicted affinity, thus defining the Applicability Domain metrics explicitly. We evaluate SimBoost and SimBoostQuant on two established Drug–Target interaction benchmark datasets and one new dataset that we propose to use as a benchmark for read-across cheminformatics applications. We demonstrate that our methods outperform the previously reported models across the studied datasets.
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SimBoost: a read-across approach for predicting Drug–Target binding affinities using gradient boosting machines
Journal of Cheminformatics, 2017Co-Authors: Marten Heidemeyer, Artem Cherkasov, Fuqiang Ban, Martin EsterAbstract:Computational prediction of the interaction between Drugs and Targets is a standing challenge in the field of Drug discovery. A number of rather accurate predictions were reported for various binary Drug–Target benchmark datasets. However, a notable drawback of a binary representation of interaction data is that missing endpoints for non-interacting Drug–Target pairs are not differentiated from inactive cases, and that predicted levels of activity depend on pre-defined binarization thresholds. In this paper, we present a method called SimBoost that predicts continuous (non-binary) values of binding affinities of compounds and proteins and thus incorporates the whole interaction spectrum from true negative to true positive interactions. Additionally, we propose a version of the method called SimBoostQuant which computes a prediction interval in order to assess the confidence of the predicted affinity, thus defining the Applicability Domain metrics explicitly. We evaluate SimBoost and SimBoostQuant on two established Drug–Target interaction benchmark datasets and one new dataset that we propose to use as a benchmark for read-across cheminformatics applications. We demonstrate that our methods outperform the previously reported models across the studied datasets.
