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TIME Project: Design and development of a disruptive technology platform to evaluate the kinetic profile of GPCRs
The purpose of TIME project is to develop a robust and highly sensitive binding kinetics platform that can be applied to high throughput kinetic screening and kinetic selectivity profiling to guide the affinity and kinetic optimization of GPCR drugs. Enzymlogic’s GPCR binding kinetics platform will allow the study of how long drugs stay bound to their targets, helping researchers optimize the temporal and functional response profiles of future drug candidates.
Beyond potency measurements: what is the value of binding kinetics in drug discovery?
Drugs’ binding kinetics determine how fast a drug and its target associate and dissociate. In the drug discovery process, researchers focus on how strongly a potential drug binds with its target rather than on how long the drug remains bound to the target (residence time).
However, the kinetics of the interaction between a drug and its target, and particularly residence time, have a strong influence on the clinical drug efficacy, safety, duration of action and therapeutic differentiation. Application of binding kinetic information is key to understanding how to discover better drugs and reduce costs by withdrawing ineffective or unsafe molecules earlier in the drug discovery process.
Compounds with identical affinity for a given GPCR can exhibit very different kinetic profiles, which may result in the differentiation of the clinical responses.
Sustained GPCR signaling
G protein-coupled receptors (GPCRs) are the largest class of membrane proteins in the human genome. These receptors sense a variety of signaling molecules, activate multiple intracellular signal pathways, and act as therapeutic targets of over 40% of marketed drugs. These proteins are active in just about every organ system and present a wide range of opportunities as therapeutic targets in areas including cardiovascular disease, asthma, diabetes, pain, obesity, Alzheimer's disease, Parkinson's disease and several forms of cancer.
Pharmacological characterization of GPCR ligands has traditionally focused on potency and efficacy, where concentration-dependent parameters are measured at equilibrium. There is, however, a growing evidence for the physiological relevance of the temporal aspects of ligand-GPCRs interactions and the need of applying binding kinetics to optimize the temporal and functional response profiles of future drug candidates.
The TIME project has been set up as part of the NEOTEC Program (EXP-00085751 / SNEO-20151089), and is funded with €175.000 from the Centre for the Development of Industrial Technology (CDTI). CDTI is a Public Business Entity, answering to the Spanish Ministry of Economy and Competitiveness, which fosters the technological development and innovation of Spanish companies. CDTI channels the funding and support applications for national and international R&D projects of Spanish companies.
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