The Generations of Sequencing Technologies: An Overview

The world has now entered into a new era of genomics because of the continued advancements in the next generation high throughput sequencing technologies, which includes sequencing by synthesis-fluorescent in situ sequencing (FISSEQ), pyrosequencing, sequencing by ligation using polony amplification, supported oligonucleotide detection (SOLiD), sequencing by hybridization along with sequencing by ligation, and nanopore technology. Great impacts of these methods can be seen for solving the genome related problems of plant and animal kingdom that will open the door of a new era of genomics. This may ultimately overcome the Sanger sequencing that ruled for 30 years. NGS is expected to advance and make the drug discovery process more rapid.

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ReAction!

10.1093/oso/9780195326925.001.0001 ◽

2009 ◽

Author(s):

Mark A. Griep ◽

Marjorie L. Mikasen

Keyword(s):

Drug Discovery ◽

Chemical Weapons ◽

Trial And Error ◽

Discovery Process ◽

Drug Discovery Process ◽

Special Effects ◽

Invisible Man ◽

Feature Films ◽

The World ◽

Chemical Companies

ReAction! gives a scientist's and artist's response to the dark and bright sides of chemistry found in 140 films, most of them contemporary Hollywood feature films but also a few documentaries, shorts, silents, and international films. Even though there are some examples of screen chemistry between the actors and of behind-the-scenes special effects, this book is really about the chemistry when it is part of the narrative. It is about the dualities of Dr. Jekyll vs. inventor chemists, the invisible man vs. forensic chemists, chemical weapons vs. classroom chemistry, chemical companies that knowingly pollute the environment vs. altruistic research chemists trying to make the world a better place to live, and, finally, about people who choose to experiment with mind-altering drugs vs. the drug discovery process. Little did Jekyll know when he brought the Hyde formula to his lips that his personality split would provide the central metaphor that would come to describe chemistry in the movies. This book explores the two movie faces of this supposedly neutral science. Watching films with chemical eyes, Dr. Jekyll is recast as a chemist engaged in psychopharmaceutical research but who becomes addicted to his own formula. He is balanced by the often wacky inventor chemists who make their discoveries by trial-and-error.

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Radioligand Binding Assays in the Drug Discovery Process: Potential Pitfalls of High Throughput Screenings

Arzneimittelforschung ◽

10.1055/s-0031-1300020 ◽

2011 ◽

Vol 51 (02) ◽

pp. 169-173 ◽

Cited By ~ 1

Author(s):

François Noël ◽

Dayde Mendonça-Silva ◽

Luis Quintas

Keyword(s):

Drug Discovery ◽

High Throughput ◽

Radioligand Binding ◽

Discovery Process ◽

Drug Discovery Process ◽

Binding Assays

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A Novel High-Throughput FLIPR Tetra–Based Method for Capturing Highly Confluent Kinetic Data for Structure–Kinetic Relationship Guided Early Drug Discovery

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/24725552211000676 ◽

2021 ◽

pp. 247255522110006

Author(s):

Puneet Khurana ◽

Lisa McWilliams ◽

Jonathan Wingfield ◽

Derek Barratt ◽

Bharath Srinivasan

Keyword(s):

Parameter Estimation ◽

Drug Discovery ◽

High Throughput ◽

Kinetic Data ◽

Time Course ◽

Kinetic Studies ◽

Discovery Process ◽

Drug Discovery Process ◽

Traditional Methods ◽

Kinetic Relationship

Target engagement by small molecules is necessary for producing a physiological outcome. In the past, a lot of emphasis was placed on understanding the thermodynamics of such interactions to guide structure–activity relationships. It is becoming clearer, however, that understanding the kinetics of the interaction between a small-molecule inhibitor and the biological target [structure–kinetic relationship (SKR)] is critical for selection of the optimum candidate drug molecule for clinical trial. However, the acquisition of kinetic data in a high-throughput manner using traditional methods can be labor intensive, limiting the number of molecules that can be tested. As a result, in-depth kinetic studies are often carried out on only a small number of compounds, and usually at a later stage in the drug discovery process. Fundamentally, kinetic data should be used to drive key decisions much earlier in the drug discovery process, but the throughput limitations of traditional methods preclude this. A major limitation that hampers acquisition of high-throughput kinetic data is the technical challenge in collecting substantially confluent data points for accurate parameter estimation from time course analysis. Here, we describe the use of the fluorescent imaging plate reader (FLIPR), a charge-coupled device (CCD) camera technology, as a potential high-throughput tool for generating biochemical kinetic data with smaller time intervals. Subsequent to the design and optimization of the assay, we demonstrate the collection of highly confluent time-course data for various kinase protein targets with reasonable throughput to enable SKR-guided medicinal chemistry. We select kinase target 1 as a special case study with covalent inhibition, and demonstrate methods for rapid and detailed analysis of the resultant kinetic data for parameter estimation. In conclusion, this approach has the potential to enable rapid kinetic studies to be carried out on hundreds of compounds per week and drive project decisions with kinetic data at an early stage in drug discovery.

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High-Throughput siRNA-Based Functional Target Validation

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057104263533 ◽

2004 ◽

Vol 9 (4) ◽

pp. 286-293 ◽

Cited By ~ 20

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.

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Chemical fragment arrays for rapid druggability assessment

Chemical Communications ◽

10.1039/c5cc10457b ◽

2016 ◽

Vol 52 (58) ◽

pp. 9067-9070 ◽

Cited By ~ 12

Author(s):

J. Aretz ◽

Y. Kondoh ◽

K. Honda ◽

U. R. Anumala ◽

M. Nazaré ◽

...

Keyword(s):

Drug Discovery ◽

High Throughput ◽

High Throughput Screening ◽

Discovery Process ◽

Drug Discovery Process ◽

Target Proteins

Incorporation of early druggability assessment in the drug discovery process provides a means to prioritize target proteins for high-throughput screening.

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Managing laboratory automation: integration and informatics in drug discovery

Journal of Automated Methods and Management in Chemistry ◽

10.1155/s1463924600000298 ◽

2000 ◽

Vol 22 (6) ◽

pp. 169-170 ◽

Cited By ~ 2

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.

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A Novel High-Throughput FLIPR Tetra Based Method for Capturing Highly Confluent Kinetic Data for Structure-Kinetic Relationship Guided Early Drug Discovery

10.26434/chemrxiv.13347524.v1 ◽

2020 ◽

Author(s):

Puneet Khurana ◽

Lisa McWilliams ◽

Jonathan Wingfield ◽

Derek Barratt ◽

Bharath Srinivasan

Keyword(s):

Parameter Estimation ◽

Drug Discovery ◽

High Throughput ◽

Kinetic Data ◽

Time Course ◽

Kinetic Studies ◽

Discovery Process ◽

Drug Discovery Process ◽

Traditional Methods ◽

Kinetic Relationship

<p>Target engagement by small-molecules is necessary for producing a physiological outcome. In the past, a lot of emphasis was placed on understanding the thermodynamics of such interactions to guide structure-activity relationship. However, it is becoming clearer that understanding the kinetics of the interaction between a small molecule inhibitor and the biological target (structure kinetic relationship, SKR) is critical for selection of the optimum candidate drug molecule for clinical trial. However, the acquisition of kinetic data in high-throughput manner using traditional methods can be labor intensive, limiting the number of molecules that can be tested. As a result, in depth kinetic studies are often carried out only on a small number of compounds and, usually, at a later stage in the drug discovery process. Fundamentally, kinetic data should be used to drive key decisions much earlier in the drug discovery process but the throughput limitations of traditional methods precludes this. A major limitation that hampers acquisition of high-throughput kinetic data is the technical challenge in collecting substantially confluent datapoints for accurate parameter estimation from time-course analysis. Here we describe the use of Fluorescent Imaging Plate Reader (FLIPR), a CCD camera technology, as a potential high-throughput tool for generating biochemical kinetic data with smaller time-intervals. Subsequent to the design and optimization of the assay, we demonstrate the collection of highly confluent time-course data for various kinase protein targets with reasonable throughput to enable SKR-guided medicinal chemistry. We select kinase target 1 as a special case study with covalent inhibition and demonstrate methods for rapid and detailed analysis of the resultant kinetic data for parameter estimation . In conclusion, this approach has the potential to enable rapid kinetic studies to be carried out on 100's of compounds per week and drive project decisions with kinetic data at an early stage in drug discovery.</p>

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Cracking the genetic code of our cities: researchers around the world aim to map the urban genome

Microbiology Australia ◽

10.1071/ma16064 ◽

2016 ◽

Vol 37 (4) ◽

pp. 194

Author(s):

Sofia Ahsanuddin ◽

Ebrahim Afshinnekoo ◽

Christopher E. Mason

Keyword(s):

Genetic Code ◽

High Throughput ◽

Light Microscope ◽

Scientific Revolution ◽

High Throughput Sequencing ◽

Cost Effective ◽

The Past ◽

Sequencing Technologies ◽

The World ◽

The One

It is rare to say that one has lived through a revolution, but we are all living through one right now. High-throughput sequencing technologies have become cheaper and more cost-effective over the past decade, moving even faster than Moore’s Law for computer power (doubling every 18 months). Because sequencers are modern-day 'molecular microscopes', scientists believe that we are currently experiencing a scientific revolution similar to the one sparked by Antonie van Leeuwenhoek’s invention of the world’s first light microscope in the 17th century.

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A Novel High-Throughput FLIPR Tetra Based Method for Capturing Highly Confluent Kinetic Data for Structure-Kinetic Relationship Guided Early Drug Discovery

10.26434/chemrxiv.13347524 ◽

2020 ◽

Author(s):

Puneet Khurana ◽

Lisa McWilliams ◽

Jonathan Wingfield ◽

Derek Barratt ◽

Bharath Srinivasan

Keyword(s):

Parameter Estimation ◽

Drug Discovery ◽

High Throughput ◽

Kinetic Data ◽

Time Course ◽

Kinetic Studies ◽

Discovery Process ◽

Drug Discovery Process ◽

Traditional Methods ◽

Kinetic Relationship

<p>Target engagement by small-molecules is necessary for producing a physiological outcome. In the past, a lot of emphasis was placed on understanding the thermodynamics of such interactions to guide structure-activity relationship. However, it is becoming clearer that understanding the kinetics of the interaction between a small molecule inhibitor and the biological target (structure kinetic relationship, SKR) is critical for selection of the optimum candidate drug molecule for clinical trial. However, the acquisition of kinetic data in high-throughput manner using traditional methods can be labor intensive, limiting the number of molecules that can be tested. As a result, in depth kinetic studies are often carried out only on a small number of compounds and, usually, at a later stage in the drug discovery process. Fundamentally, kinetic data should be used to drive key decisions much earlier in the drug discovery process but the throughput limitations of traditional methods precludes this. A major limitation that hampers acquisition of high-throughput kinetic data is the technical challenge in collecting substantially confluent datapoints for accurate parameter estimation from time-course analysis. Here we describe the use of Fluorescent Imaging Plate Reader (FLIPR), a CCD camera technology, as a potential high-throughput tool for generating biochemical kinetic data with smaller time-intervals. Subsequent to the design and optimization of the assay, we demonstrate the collection of highly confluent time-course data for various kinase protein targets with reasonable throughput to enable SKR-guided medicinal chemistry. We select kinase target 1 as a special case study with covalent inhibition and demonstrate methods for rapid and detailed analysis of the resultant kinetic data for parameter estimation . In conclusion, this approach has the potential to enable rapid kinetic studies to be carried out on 100's of compounds per week and drive project decisions with kinetic data at an early stage in drug discovery.</p>

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