2.5 CuAAC and Metal-Free 1,3-Dipolar Huisgen Cycloadditions in Drug Discovery

2022 ◽  
Author(s):  
K. M. Kacprzak ◽  
I. Skiera ◽  
J. Rutkowski
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Click Chemistry ◽  
Combinatorial Chemistry ◽  
High Throughput Screening ◽  
Dipolar Cycloaddition ◽  
Discovery Process ◽  
Metal Free ◽  
The Stability

AbstractProclaimed by Sharpless in 2001, the manifesto of click chemistry philosophy shifted the focus from target-oriented to drug-like-oriented synthesis, and has enormously accelerated the drug-discovery process over the last two decades. Copper(I)-catalyzed and metal-free versions of the Huisgen 1,3-dipolar cycloaddition of azides and alkynes have become the reference click chemistry synthetic tools. These processes are adaptable to various drug-design modes such as kinetic target guided synthesis (in situ click chemistry assembling; KTGS), combinatorial chemistry/high-throughput-screening approaches, or structure-based rational projecting. Moreover, the facile click chemistry derivatization of natural or synthetic products, linking molecules or improving the stability of leads by installation of 1,2,3-triazoles, is another important stream of bioactivities. This review is intended to provide a general overview of click-chemistry-powered drug design, with dozens of successful examples resulting in the discovery of nanomolar-active 1,2,3-triazoles in every stage of drug development.

scholarly journals Managing laboratory automation: integration and informatics in drug discovery

2000 ◽  
Vol 22 (6) ◽  
pp. 169-170 ◽  
Author(s):  
Charles J. Manly
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Combinatorial Chemistry ◽  
High Throughput Screening ◽  
Laboratory Automation ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
Modern Drug

Drug discovery today requires the focused use of laboratory automation and other resources in combinatorial chemistry and high-throughput screening (HTS). The ultimate value of both combinatorial chemistry and HTS technologies and the lasting impact they will have on the drug discovery process is a chapter that remains to be written. Central to their success and impact is how well they are integrated with each other and with the rest of the drug discovery processes-informatics is key to this success. This presentation focuses on informatics and the integration of the disciplines of combinatorial chemistry and HTS in modern drug discovery. Examples from experiences at Neurogen from the last five years are described.

8 Sydnone-Based Cycloadditions in Click Chemistry

2022 ◽  
Author(s):  
F. Friscourt
Keyword(s):  
Drug Discovery ◽  
Click Chemistry ◽  
Click Reaction ◽  
Living Cells ◽  
Dipolar Cycloaddition ◽  
Metal Catalysis ◽  
Metal Free ◽  
Fluorogenic Probes ◽  
Release Strategy

AbstractThe 1,3-dipolar cycloaddition of sydnones (1,2,3-oxadiazolium-5-olates) with dipolarophiles, such as alkynes, has recently emerged as a versatile click reaction, with applications ranging from the mild and regioselective preparation of polysubstituted pyrazoles for drug discovery to the metal-free bioorthogonal ligation of biomacromolecules in living cells. This chapter reviews the importance of metal catalysis for controlling the regioselectivity of the copper-mediated reaction (CuSAC), as well as the development of fluorogenic probes, the click and release strategy, and photo-triggered ligations based on strain-promoted sydnone–alkyne cycloadditions (SPSAC).

scholarly journals Integration of an In Situ MALDI-Based High-Throughput Screening Process: A Case Study with Receptor Tyrosine Kinase c-MET

2017 ◽  
Vol 22 (10) ◽  
pp. 1203-1210 ◽  
Author(s):  
Katrin Beeman ◽  
Jens Baumgärtner ◽  
Manuel Laubenheimer ◽  
Karlheinz Hergesell ◽  
Martin Hoffmann ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
High Throughput Screening ◽  
Maldi Ms ◽  
Kinase Assay ◽  
Label Free ◽  
Screening Process ◽  
Label Free Detection ◽  
Ic50 Values

Mass spectrometry (MS) is known for its label-free detection of substrates and products from a variety of enzyme reactions. Recent hardware improvements have increased interest in the use of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS for high-throughput drug discovery. Despite interest in this technology, several challenges remain and must be overcome before MALDI-MS can be integrated as an automated “in-line reader” for high-throughput drug discovery. Two such hurdles include in situ sample processing and deposition, as well as integration of MALDI-MS for enzymatic screening assays that usually contain high levels of MS-incompatible components. Here we adapt our c-MET kinase assay to optimize for MALDI-MS compatibility and test its feasibility for compound screening. The pros and cons of the Echo (Labcyte) as a transfer system for in situ MALDI-MS sample preparation are discussed. We demonstrate that this method generates robust data in a 1536-grid format. We use the MALDI-MS to directly measure the ratio of c-MET substrate and phosphorylated product to acquire IC50 curves and demonstrate that the pharmacology is unaffected. The resulting IC50 values correlate well between the common label-based capillary electrophoresis and the label-free MALDI-MS detection method. We predict that label-free MALDI-MS-based high-throughput screening will become increasingly important and more widely used for drug discovery.

Protein-Ligand Docking Methodologies and Its Application in Drug Discovery

2016 ◽  
pp. 196-219
Author(s):  
Sanchaita Rajkhowa ◽  
Ramesh C. Deka
Keyword(s):  
Molecular Docking ◽  
Drug Discovery ◽  
Drug Design ◽  
High Throughput Screening ◽  
Docking Studies ◽  
Stable Complex ◽  
Scoring Functions ◽  
Binding Modes ◽  
Structure Based Drug Design ◽  
Modern Drug

Molecular docking is a key tool in structural biology and computer-assisted drug design. Molecular docking is a method which predicts the preferred orientation of a ligand when bound in an active site to form a stable complex. It is the most common method used as a structure-based drug design. Here, the authors intend to discuss the various types of docking methods and their development and applications in modern drug discovery. The important basic theories such as sampling algorithm and scoring functions have been discussed briefly. The performances of the different available docking software have also been discussed. This chapter also includes some application examples of docking studies in modern drug discovery such as targeted drug delivery using carbon nanotubes, docking of nucleic acids to find the binding modes and a comparative study between high-throughput screening and structure-based virtual screening.

scholarly journals The Effects of Combinatorial Chemistry and Technologies on Drug Discovery and Biotechnology – a Mini Review

2014 ◽  
Vol 13 (2) ◽  
pp. 87-108 ◽  
Author(s):  
Pierfausto Seneci ◽  
Giorgio Fassina ◽  
Vladimir Frecer ◽  
Stanislav Miertus
Keyword(s):  
Drug Discovery ◽  
Drug Design ◽  
Expert Opinion ◽  
High Throughput ◽  
Combinatorial Chemistry ◽  
Rational Design ◽  
Combinatorial Libraries ◽  
Computer Assisted ◽  
Future Trends ◽  
The Impact

Abstract The review will focus on the aspects of combinatorial chemistry and technologies that are more relevant in the modern pharmaceutical process. An historical, critical introduction is followed by three chapters, dealing with the use of combinatorial chemistry/high throughput synthesis in medicinal chemistry; the rational design of combinatorial libraries using computer-assisted combinatorial drug design; and the use of combinatorial technologies in biotechnology. The impact of “combinatorial thinking” in drug discovery in general, and in the examples reported in details, is critically discussed. Finally, an expert opinion on current and future trends in combinatorial chemistry and combinatorial technologies is provided.

High-Throughput siRNA-Based Functional Target Validation

2004 ◽  
Vol 9 (4) ◽  
pp. 286-293 ◽  
Author(s):  
Hong Xin ◽  
Alejandro Bernal ◽  
Frank A. Amato ◽  
Albert Pinhasov ◽  
Jack Kauffman ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
High Throughput Screening ◽  
Target Genes ◽  
Discovery Process ◽  
Target Validation ◽  
Drug Discovery Process ◽  
Functional Identification ◽  
Screening Process ◽  
Lead Compounds

The drug discovery process pursued by major pharmaceutical companies for many years starts with target identification followed by high-throughput screening (HTS) with the goal of identifying lead compounds. To accomplish this goal, significant resources are invested into automation of the screening process or HTS. Robotic systems capable of handling thousands of data points per day are implemented across the pharmaceutical sector. Many of these systems are amenable to handling cell-based screening protocols as well. On the other hand, as companies strive to develop innovative products based on novel mechanisms of action(s), one of the current bottlenecks of the industry is the target validation process. Traditionally, bioinformatics and HTS groups operate separately at different stages of the drug discovery process. The authors describe the convergence and integration of HTS and bioinformatics to perform high-throughput target functional identification and validation. As an example of this approach, they initiated a project with a functional cell-based screen for a biological process of interest using libraries of small interfering RNA (siRNA) molecules. In this protocol, siRNAs function as potent gene-specific inhibitors. siRNA-mediated knockdown of the target genes is confirmed by TaqMan analysis, and genes with impacts on biological functions of interest are selected for further analysis. Once the genes are confirmed and further validated, they may be used for HTS to yield lead compounds.

scholarly journals Fast tracking drug development: balancing risks and rewards

2002 ◽  
Vol 23 (5) ◽  
pp. 20
Author(s):  
Harry Majewski
Keyword(s):  
Drug Design ◽  
Drug Development ◽  
High Throughput ◽  
Combinatorial Chemistry ◽  
High Throughput Screening ◽  
Target Discovery ◽  
New Therapies ◽  
Fast Tracking ◽  
Great Hope

The biotechnology revolution offers great hope for new therapies based on rational approaches to target discovery and drug design based on genomics, proteomics, advanced chemistry (3-D modelling, combinatorial chemistry) and high throughput screening.

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