Novel Trends in High-Throughput Screening

High-throughput screening (HTS) is one of the newest techniques used in drug design and may be applied in biological and chemical sciences. This method, due to utilization of robots, detectors and software that regulate the whole process, enables a series of analyses of chemical compounds to be conducted in a short time and the affinity of biological structures which is often related to toxicity to be defined. Since 2008 we have implemented the automation of this technique and as a consequence, the possibility to examine 100,000 compounds per day. The HTS method is more frequently utilized in conjunction with analytical techniques such as NMR or coupled methods e.g., LC-MS/MS. Series of studies enable the establishment of the rate of affinity for targets or the level of toxicity. Moreover, researches are conducted concerning conjugation of nanoparticles with drugs and the determination of the toxicity of such structures. For these purposes there are frequently used cell lines. Due to the miniaturization of all systems, it is possible to examine the compound’s toxicity having only 1–3 mg of this compound. Determination of cytotoxicity in this way leads to a significant decrease in the expenditure and to a reduction in the length of the study.

Adaptation of High-Throughput Screening in Drug Discovery—Toxicological Screening Tests

Benzimidazole: an emerging scaffold for analgesic and anti-inflammatory agents.

In silico methods and tools for drug discovery.

This two-part review examines how automation has contributed to different aspects of discovery in the chemical sciences. In this first part, we describe a classification for discoveries of physical matter (molecules, materials, devices), processes, and models and how they are unified as search problems. We then introduce a set of questions and considerations relevant to assessing the extent of autonomy. Finally, we describe many case studies of discoveries accelerated by or resulting from computer assistance and automation from the domains of synthetic chemistry, drug discovery, inorganic chemistry, and materials science. These illustrate how rapid advancements in hardware automation and machine learning continue to transform the nature of experimentation and modelling. 
Part two reflects on these case studies and identifies a set of open challenges for the field.

Autonomous discovery in the chemical sciences part I: Progress

The search for novel TRPV1-antagonists: From carboxamides to benzimidazoles and indazolones

The need for a high degree of flexibility within compound screening is a requirement throughout the drug discovery industry. The demands made of automation technology are becoming increasingly sophisticated as assay formats diversify and confidence in screening automation grows. To meet these demands for high-performance and flexibility, MSD with RTS Life Science have developed and installed a dual-robot arm screening system at our Terlings Park site to support early stage drug discovery. Plate transport on the system is via two articulated robotic Staubli arms. The system has two operating modes, combined, with the entire system operating in unison; and independent with each robot arm acting independently to perform two different screens in parallel. Additional flexibility is provided by the SPRINT software ‘dynamic batch scheduling’ feature. This allows for the scheduling of multiple screens to run automatically and for extra plates to be added and new screens to be added once the system is running with...

https://jla.sagepub.com/content/12/2/115.full.pdf

Implementation of a High Specification Dual-Arm Robotic Platform to Meet Flexible Screening Needs

Enzymes are often considered less "druggable" targets than ligand-regulated proteins such as G-protein-coupled receptors, ion channels, or other hormone receptors. Reasons for this include cellular location (intracellular vs. cell surface), typically lower affinities for the binding of small molecules compared to ligand-specific receptors, and binding (catalytic) sites that are often charged or highly polar. A practical drawback to the discovery of compounds targeting enzymes is that screening of compound libraries is typically carried out in cell-free activity assays using purified protein in an inherently artificial environment. Cell-based assays, although often arduous to design for enzyme targets, are the preferred discovery tool for the screening of large compound libraries. The authors have recently described a novel cell-based approach to screening for inhibitors of a phosphatase enzyme and now report on the development and implementation of a homogeneous 3456-well plate assay for D-amino acid oxidase (DAO). Human DAO was stably expressed in Chinese hamster ovary (CHO) cells, and its activity was measured as the amount of hydrogen peroxide detected in the growth medium following feeding the cells with D-serine. In less than 12 weeks, the authors proved the concept in 96-and then 384-well formats, miniaturized the assay to the 3456-well (nanoplate) scale, and screened a library containing more than 1 million compounds. They have identified several cell-permeable inhibitors of DAO from this cell-based high-throughput screening, which provided the discovery program with a few novel and attractive lead structures.

https://journals.sagepub.com/doi/pdf/10.1177/1087057106288181

A cell-based ultra-high-throughput screening assay for identifying inhibitors of D-amino acid oxidase

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The search for novel TRPV1-antagonists: From carboxamides to benzimidazoles and indazolones

Implementation of a High Specification Dual-Arm Robotic Platform to Meet Flexible Screening Needs

A cell-based ultra-high-throughput screening assay for identifying inhibitors of D-amino acid oxidase