Abstract
Medicinal chemistry plays a fundamental and underlying role in chemical biology, pharmacology, and medicine to discover safe and efficacious drugs. Small molecule medicinal chemistry relies on iterative learning cycles composed of compound design, synthesis, testing, and data analysis to provide new chemical probes and lead compounds for novel and druggable targets. Using traditional approaches, the time from hypothesis to obtaining the results can be protracted, thus limiting the number of compounds that can be advanced into clinical studies. This challenge can be tackled with the recourse of enabling technologies that are showing great potential in improving the drug discovery process. In this Perspective, we highlight recent developments toward innovative medicinal chemistry strategies based on continuous flow systems coupled with automation and bioassays. After a discussion of the aims and concepts, we describe equipment and representative examples of automated flow systems and end-to-end prototypes realized to expedite medicinal chemistry discovery cycles.
Highlights
Medicinal chemistry plays a fundamental and underlying role in chemical biology, pharmacology, and medicine to discover safe and efficacious drugs
We recently reported the integration of flow synthesizers, automation, analytical, and computational tools for the generation of chiral tetracyclic tetrahydroquinolines as novel Pregnane X Receptor (PXR) agonists (Figure 17).[123]
By using a rapid microscale flow synthesis coupled with size-exclusion chromatography (SEC)-mass spectrometry (MS) technology, the modular platform solved the main limitations of the conventional protein-directed dynamic combinatorial chemistry (DCC), including the poor reactivity of inhibitors at low concentrations, the reduction of protein activity or decomposition of inhibitors for long equilibration times, as well as the low throughput of currently available analytical detection methods
Summary
Automation in drug discovery is not a new concept.[25]. Solidphase peptide synthesis was made automated in the 1960s. Organic synthesis applications.[29,30,67−75] Beyond the simple management of reagent selection and compound collection for library building, machine-assisted flow devices can be applied for predictive and decision-making actions in closedloop mode for both medicinal chemistry learning and process optimization.[12,31] this area is still in a nascent state, recent advances have propelled different manufactures of flow equipment, research groups, and specialized companies into the development of specific software and programming languages for automated drug discovery platforms.[76] Open-source software and computer-aided approaches for automating flow systems are rapidly growing and include suites as LabVIEW,[77] MatLab,[78] LeyLab,[29] OpenFlowChem,[60] ChemOS,[79] and Chemputer.[80]. Numerous examples of droplet microfluidic assays for synthetic biology applications, including DNA assembly, transformation/transfection, culturing, cell sorting, phenotypic assays, artificial cells and genetic circuits have been reported and recently reviewed by Gach et al.[101]
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