How High-Throughput Medicinal Chemistry Can Expedite Lead Discovery, Lead Optimization, and Beyond

2008 ◽  
pp. 151-164
Author(s):  
Rongshi Li
Keyword(s):  
High Throughput ◽  
Medicinal Chemistry ◽  
Lead Optimization ◽  
Lead Discovery

scholarly journals A Direct-to-Biology High-Throughput Chemistry Approach to Reactive Fragment Screening

2021 ◽  
Author(s):  
Ross P. Thomas ◽  
Rachel E. Heap ◽  
Francesca Zappacosta ◽  
Emma K. Grant ◽  
Peter Pogany ◽  
...  
Keyword(s):  
High Throughput ◽  
Medicinal Chemistry ◽  
Binding Pocket ◽  
Rapid Identification ◽  
Rapid Synthesis ◽  
Iterative Design ◽  
Fragment Screening ◽  
Hit Rate ◽  
Chemical Tools ◽  
Screening Platform

<p>Methods for rapid identification of chemical tools are essential for the validation of emerging targets and to provide medicinal chemistry starting points for the development of <a>new medicines. Here, we report a screening platform that combines ‘direct-to-biology’ high-throughput chemistry (D2B-HTC) with photoreactive covalent fragments. The platform enabled the rapid synthesis of >1000 PhotoAffinity Bits (HTC-PhABits) in 384-well plates. Screening the HTC-PhABit library with </a>carbonic anhydrase I (CAI) afforded 7 hits (0.7% hit rate), which were found to covalently crosslink in the Zn<sup>2+</sup> binding pocket. A powerful advantage of the D2B-HTC screening platform is the ability to rapidly perform iterative design-make-test cycles, accelerating the development and optimisation of chemical tools and medicinal chemistry starting points with little investment of resource.</p>

scholarly journals A High-Throughput Cellular Screening Assay for Small-Molecule Inhibitors and Activators of Cytoplasmic Dynein-1-Based Cargo Transport

2020 ◽  
Vol 25 (9) ◽  
pp. 985-999
Author(s):  
John Vincent ◽  
Marian Preston ◽  
Elizabeth Mouchet ◽  
Nicolas Laugier ◽  
Adam Corrigan ◽  
...  
Keyword(s):  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Small Molecule Inhibitors ◽  
Cytoplasmic Dynein ◽  
Lead Discovery ◽  
Screening Assay ◽  
Age Related ◽  
The Uk

Cytoplasmic dynein-1 (hereafter dynein) is a six-subunit motor complex that transports a variety of cellular components and pathogens along microtubules. Dynein’s cellular functions are only partially understood, and potent and specific small-molecule inhibitors and activators of this motor would be valuable for addressing this issue. It has also been hypothesized that an inhibitor of dynein-based transport could be used in antiviral or antimitotic therapy, whereas an activator could alleviate age-related neurodegenerative diseases by enhancing microtubule-based transport in axons. Here, we present the first high-throughput screening (HTS) assay capable of identifying both activators and inhibitors of dynein-based transport. This project is also the first collaborative screening report from the Medical Research Council and AstraZeneca agreement to form the UK Centre for Lead Discovery. A cellular imaging assay was used, involving chemically controlled recruitment of activated dynein complexes to peroxisomes. Such a system has the potential to identify molecules that affect multiple aspects of dynein biology in vivo. Following optimization of key parameters, the assay was developed in a 384-well format with semiautomated liquid handling and image acquisition. Testing of more than 500,000 compounds identified both inhibitors and activators of dynein-based transport in multiple chemical series. Additional analysis indicated that many of the identified compounds do not affect the integrity of the microtubule cytoskeleton and are therefore candidates to directly target the transport machinery.

High throughput metabolic stability screen for lead optimization in drug discovery

2006 ◽  
Vol 833 (2) ◽  
pp. 165-173 ◽  
Author(s):  
X TONG ◽  
S XU ◽  
S ZHENG ◽  
J PIVNICHNY ◽  
J MARTIN ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Metabolic Stability ◽  
Lead Optimization

scholarly journals Stability of Screening Compounds in Wet DMSO

2008 ◽  
Vol 13 (10) ◽  
pp. 999-1006 ◽  
Author(s):  
Caroline Engeloch ◽  
Ulrich Schopfer ◽  
Ingo Muckenschnabel ◽  
Francois Le Goff ◽  
Hervé Mees ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Medicinal Chemistry ◽  
Storage Conditions ◽  
Pragmatic Approach ◽  
Analytical Quality ◽  
The Past ◽  
Effect Of Water ◽  
The Impact

The impact of storage conditions on compound stability and compound solubility has been debated intensely over the past 5 years. At Novartis, the authors decided to opt for a storage concept that can be considered controversial because they are using a DMSO/water (90/10) mixture as standard solvent. To assess the effect of water in DMSO stocks on compound stability, the authors monitored the purity of a subset of 1404 compounds from ongoing medicinal chemistry projects over several months. The study demonstrated that 85% of the compounds were stable in wet DMSO over a 2-year period at 4 °C. This result validates the storage concept developed at Novartis as a pragmatic approach that takes advantage of the benefits of DMSO/water mixtures while mediating the disadvantages. In addition, the authors describe how purity data collected over the course of the chemical validation of high-throughput screening actives are used to improve the analytical quality of the Novartis screening deck. ( Journal of Biomolecular Screening 2008:999-1006)

PAINS: Relevance to Tool Compound Discovery and Fragment-Based Screening

2013 ◽  
Vol 66 (12) ◽  
pp. 1483 ◽  
Author(s):  
Jonathan B. Baell ◽  
Lori Ferrins ◽  
Hendrik Falk ◽  
George Nikolakopoulos
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Medicinal Chemistry ◽  
Great Caution ◽  
Starting Point ◽  
Very High ◽  
Assay Interference

Pan assay interference compounds (PAINS) are readily discovered in any bioassay and can appear to give selective and optimisable hits. The most common PAINS can be readily recognised by their structure. However, there are compounds that closely resemble PAINS that are not specifically recognised by the PAINS filters. In addition, highly reactive compounds are not encoded for in the PAINS filters because they were excluded from the high-throughput screening (HTS) library used to develop the filters and so were never present to provide indicting data. A compounding complication in the area is that very occasionally a PAINS compound may serve as a viable starting point for progression. Despite such an occasional example, the literature is littered with an overwhelming number of examples of compounds that fail to progress and were probably not optimisable in the first place, nor useful tool compounds. Thus it is with great caution and diligence that compounds possessing a known PAINS core should be progressed through to medicinal chemistry optimisation, if at all, as the chances are very high that the hits will be found to be non-progressable, often after a significant waste of resources.

Lead optimization attrition analysis (LOAA): a novel and general methodology for medicinal chemistry

2015 ◽  
Vol 20 (8) ◽  
pp. 978-987 ◽  
Author(s):  
Mark Munson ◽  
Harvey Lieberman ◽  
Elina Tserlin ◽  
Jennifer Rocnik ◽  
Jie Ge ◽  
...  
Keyword(s):  
Medicinal Chemistry ◽  
Lead Optimization ◽  
General Methodology ◽  
Attrition Analysis

scholarly journals Applications of Biophysics in High-Throughput Screening Hit Validation

2014 ◽  
Vol 19 (5) ◽  
pp. 707-714 ◽  
Author(s):  
Christine Clougherty Genick ◽  
Danielle Barlier ◽  
Dominique Monna ◽  
Reto Brunner ◽  
Céline Bé ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Lessons Learned ◽  
Label Free ◽  
Lead Discovery ◽  
Binding Interaction ◽  
Differential Scanning Fluorimetry ◽  
Types Of Information ◽  
Hit Validation

For approximately a decade, biophysical methods have been used to validate positive hits selected from high-throughput screening (HTS) campaigns with the goal to verify binding interactions using label-free assays. By applying label-free readouts, screen artifacts created by compound interference and fluorescence are discovered, enabling further characterization of the hits for their target specificity and selectivity. The use of several biophysical methods to extract this type of high-content information is required to prevent the promotion of false positives to the next level of hit validation and to select the best candidates for further chemical optimization. The typical technologies applied in this arena include dynamic light scattering, turbidometry, resonance waveguide, surface plasmon resonance, differential scanning fluorimetry, mass spectrometry, and others. Each technology can provide different types of information to enable the characterization of the binding interaction. Thus, these technologies can be incorporated in a hit-validation strategy not only according to the profile of chemical matter that is desired by the medicinal chemists, but also in a manner that is in agreement with the target protein’s amenability to the screening format. Here, we present the results of screening strategies using biophysics with the objective to evaluate the approaches, discuss the advantages and challenges, and summarize the benefits in reference to lead discovery. In summary, the biophysics screens presented here demonstrated various hit rates from a list of ~2000 preselected, IC50-validated hits from HTS (an IC50 is the inhibitor concentration at which 50% inhibition of activity is observed). There are several lessons learned from these biophysical screens, which will be discussed in this article.

Prospecting Great Lakes bacteria for drug-lead discovery with high-throughput microbiome screening

Planta Medica ◽  
2015 ◽  
Vol 81 (11) ◽  
Author(s):  
M Elfeki ◽  
A Nakib ◽  
SJ Green ◽  
BT Murphy
Keyword(s):  
Great Lakes ◽  
High Throughput ◽  
Lead Discovery ◽  
Drug Lead
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