Open AccessReverse-Design toward Optimized Labeled Chemical Probes – Examples from the Endocannabinoid System
Author(s) -
Mónica Guberman,
Miroslav Kosar,
Anahid Omran,
Erick M. Carreira,
Marc Nazaré,
Uwe Grether
Publication year - 2022
Publication title -
chimia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.387
H-Index - 55
eISSN - 2673-2424
pISSN - 0009-4293
DOI - 10.2533/chimia.2022.425
Subject(s) - context (archaeology) , blueprint , computer science , biochemical engineering , computational biology , endocannabinoid system , nanotechnology , data science , risk analysis (engineering) , chemistry , engineering , medicine , biology , biochemistry , mechanical engineering , paleontology , materials science , receptor
Labeled chemical probes are of utmost importance to bring drugs from the laboratory through the clinic and ultimately to market. They support and impact all research and discovery phases: target verification and validation; assay development; lead optimization; and biomarker engagement in the context of preclinical studies and human trials. Probes should display high potency and selectivity as well as fulfill specific criteria in connection with absorption, distribution, metabolism, excretion and toxicology (ADMET) profile. Progress in fields such as imaging and proteomics increased the need for specialized probes to support drug discovery. Labeled probes carrying an additional reporter group are valuable tools to meet specific application requirements, but pose significant challenges in design and construction. In the reverse-design approach, small molecules previously optimized in medicinal chemistry programs form the basis for the generation of such high-quality probes. We discuss the reverse design concept for the generation of labeled probes targeting the endocannabinoid system (ECS), a complex lipid signaling network that plays a key role in many human health and disease conditions. The examples highlighted include diverse reporter units for a range of applications. In several cases the reported probes were the product of mutually rewarding and highly cross-fertilizing collaborations among academic and industry research programs, a strategy that can serve as a blueprint for future probe generation efforts.