High-throughput screening for new drugs

Drug discovery is one of the early stages in the long drug-development process that eventually introduces a new drug to the marketplace. High throughput screening is commonly defined as automatic testing of potential drug candidates at a rate in excess of 10,000 compounds per week. The aim of high throughput drug discovery is to test large compound collections for potentially active compounds (‘hits') in order to allow further development of compounds for pre-clinical testing (‘leads'). Screening 300,000 compounds is common and such a campaign often yields 200-300 hits from which one to two leads are eventually generated.

The high-throughput screening approach introduces industrial-scale firepower into the drug discovery process, and to a great extent, this is one of the cornerstones of the emerging industrialised drug-discovery paradigm. Surprisingly, most drugs in use in the clinic today were discovered in fairly unstructured frameworks where individual genius and serendipity by far outweighed industrial effort and structured searches.

Technological innovation has improved throughput from typical levels of 10,000 compounds per year in the 1980s to present levels in excess of 100,000 per day (known as ultra-high throughput screening, uHTS). Given the scale of these operations and their growth-rates, HTS has become directly linked to bioinformatics and cheminformatics, usually as the main source of information input for drug development.

HTS complements rational drug design
HTS is one of many tools available for drug discovery. The 1990s have been predominantly focused on rational drug discovery approaches, propagating hypothesis-driven drug discovery rather than random searches for relevant drug candidates. Within these rational approaches, the idea of Quantitative Structure Activity Relationship is the ruling paradigm. The QSAR paradigm suggests that knowledge about the desired drug target and its biological mechanism allows us to rationally design a drug, commonly referred to as designer drugs. While biological processes are seldom easy to comprehend, and the multifaceted aspects of a chemical compound's interaction with a biological target are often unpredictable, the entire QSAR approach requires vast amounts of biological and chemical experimentation in order to generate the relevant information inputs. Thus, HTS and rational design have become complementary. This complementary aspect is also seen operating in the opposite direction when the knowledge generated during QSAR analyses is used to develop assays for HTS.

From tactics to strategy
While HTS started out as a tactical tool for most pharmaceutical companies, it has now evolved into a strategy as companies attempt to move rapidly from novel targets to novel drugs. Big pharma often uses HTS to swiftly test and get solid clues about the types of drugs that will work against a certain genomic target, and potentially more importantly, what will not work. Many HTS operations have become the central strategic feeders of chemical hits in their organisations, and subsequent drug development has primarily been concerned with improving the hits generated in HTS campaigns.

Components of a successful HTS operation
There are two central components that will predict success of an HTS operation: screening assays and compound collections.

The screening assay determines the type of biological activity we are searching. Generally speaking, bad assays create bad hits, and good assays do not necessarily create good hits. This problem is usually directly related to the assay's clinical relevance.

Most high-throughput screening is concerned with simple biochemical screening - testing a chemical compound's ability to interact with a given protein target. These approaches are inherently distinct from activity in a living organism, and our ability to reach conclusions about a compound's activity and relevance in a clinical setting are limited.

Firstly, we need to consider the issue of specificity. Even if a compound interacts as desired with a target, this does not preclude its interaction in an undesirable manner with other targets, once inside the complex human body. Secondly, the problem of inherent complexity of cells and the human body needs to be considered. It is entirely possible that the biochemical interaction with a target can no longer be repeated once the interaction takes place within the environment of a living cell where all enzymes, salts, cofactors and nucleotides are present and located at their correct positions. Thirdly, most diseases are the result of a number of molecular aberrations and although our understanding of these complex interactions is constantly advancing, it is still only partial for most diseases. Of course, basing HTS screening on partial information is likely to affect the quality and relevance of the screening models chosen and thus the hits discovered.

The second component, the compounds, is potentially even more important than the assays. A chemical library can be anything from an historical collection of molecules synthesised over the years in the course of different drug programs, through combinatorial compound libraries deliberately synthesised with the purpose of reflecting a certain chemical diversity or likeliness, to collections of plant and other nature-derived materials. In most cases, the number of compounds contained therein and the breadth of chemical diversity can be used as proxies for library quality. However, when looking at a library, one should not ignore factors such as drug
likeliness (good drug properties), the number of related clusters in the library, IP considerations and availability of larger quantities of the compounds for follow-up studies.

Actors in the HTS arena
HTS has generated ample room for start-up companies to develop solutions and to become involved in the drug development process. Since the process often requires innovative thinking and approaches, many newer companies have found business opportunities in this field. Among the leaders in this field are Aurora BioSciences (San Diego, California) bought by Vertex Pharmaceuticals (Cambridge, Massachusetts) in a stock deal valued close to $600m in mid-2001. Other actors include Evotec OAI (Abingdon, UK), a major service provider, Belgium's EuroScreen, Arena Pharmaceuticals (San Diego, California), Discovery Partners (San Diego, California) and many others.

The combinatorial chemistry library segment attracted extensive attention in the mid-1990s, and today most combinatorial libraries are sold as commodities. The actors include companies such as ChemDiv (San Diego, California), Arqule (Woburn, Massachusetts), BioFocus (Sittingbourne, UK), Tripos (St. Louis, Missouri), ChemBridge (San Diego, California), Asinex (Moscow), InterBioscreen (Moscow) and others. Newer initiatives in the library arena include more exotic libraries representing previously unexplored chemical spaces such as Entomed (France) with its insect-derived libraries. In Israel, there have been few attempts to enter this scene and only some sporadic activity has been seen at universities and other research institutes to generate compound collections from plants and organisms native to the region such as microalgae from the Dead Sea and plants known to have therapeutic importance in Bedouin folklore.

HTS trends
There are a number of trends that are worthwhile following at present. Firstly, there has been a vast increase in the use of cell-based assays, allowing the testing of compounds directly in living cells. Secondly, smarter screens that incorporate both efficacy and specificity in the same assay have been developed. Thirdly, there has been the utilisation of high-throughput approaches for functional genomics. Fourthly, there are assays and approaches that start to take into account the industry's biggest problem, which remains the high attrition rates throughout the development process. Finally, systems that bridge between post-genomic activities and drug discovery are likely to quickly penetrate the market in the future, as the gene-to-drug link becomes a bottleneck in many companies.

Summary
HTS has become an integral part of drug discovery in both pharmaceutical and biotech companies. While pharma companies may be geared towards using HTS to generate information, start-ups will continue to use these systems to develop good drugs faster and cheaper. The HTS segment is lucrative for investors at a time when pipeline creation is king, because pipeline creation is exactly why HTS systems were developed.

Copyright © 2003

Dr Dan Gelvan is chief executive officer at Zetiq Technologies.

Zetiq Technologies is active in the field of  non-cytotoxic anti-cancer drugs. Offering a solution for the  high-throughput screening of cancer regulating agents, Zetiq is emerging as a central enabling solution provider in this field. For more information please visit www.zetiq.com

Published in IVCJ, a quarterly magazine from IVC Research Center covering trends and developments in Israel's high-tech industry, including IVC's Quarterly High-Tech Survey, statistical analysis, high-tech company financing and venture capital funds.