| Pharmaceutical and biopharmaceutical firms need to reduce the cost and lead time of drug development. A range of recently developed technologies makes that goal possible. |
| by Peter Gwynne and Gary Heebner |
| ADVERTISERS Affymetrix, Inc. DNA microarrays, based on the principles of semiconductor technology 408-731-5000 www.affymetrix.comRoche Applied Science kits and systems for genomics and proteomics research 317-845-2000 www.biochem.roche.comTakara Bio, Inc. kits and reagents for molecular biology research +81 77 543 7247 www.takara-bio.co.jp/englishVarian, Inc. scientific instruments, vacuum technologies, and contract manufacturing solutions for the life sciences 650-213-8000 www.varianinc.com |
| CONTENTS | |
| • | High throughput screening |
| • | Rational drug design |
| • | Combinatorial chemistry |
| • | Chemical libraries |
| • | Bioinformatics |
| • | Cheminformatics |
| • | Record keeping |
| • | BIO’s view |
Within the past few decades, the time and cost of drug development have soared. Today it typically takes about 15 years and costs up to $800 million to convert a promising new compound into a drug on the market. Those costs reflect the complexity of the process.
First, scientists must identify the molecule — a target — involved in a disease. That demands an understanding of the metabolic processes of a cell in both its normal and diseased states. The successful sequencing of the human genome has opened the way to genomics based methods for this component of drug discovery. The 30,000 or so human genes offer a vast number of possibilities for molecular researchers to consider in the search for new drugs. Understanding how the genes function and malfunction provides the key to choosing which genes to consider as targets for the discovery process.
Next, scientists have to search for another compound — a lead — that can alter the action of the target molecule. In times past, that task had the unfocused quality similar to seeking a needle in a haystack. “And in the past decade we’ve made the haystack a lot bigger,” says George Purvis, vice president and founder of CAChe Software Group, part of Fujitsu America.
Even when they are identified, active leads often lack certain properties required to become a drug. So researchers must develop chemical analogs of those compounds, synthesize them, and test them until they find a drug candidate with the desired characteristics.
That represents only a start. A compound that looks highly promising at the discovery stage can fail at several points in drug development, as it undergoes tests for toxicology and efficacy, initially in animals and then in humans. “The largest cost in drug development comes when bad side effects occur at the toxicology point,” says Steve Levine, senior director for strategic partnerships atAccelrys, a wholly owned subsidiary of Pharmacopeia.
Plainly, pharmaceutical and biopharmaceutical companies need to find ways to screen for potential problems with promising molecules at the earliest possible stage. They also need to streamline the entire process in such a way that compounds that pass the screening move quickly along the development pipeline. “In drug discovery, time is money,” says Axel Jahns, director of product management at Eppendorf. “Convenience and reliability go together.”
While they promise a cornucopia of new drugs, genomic methods alone will not reduce the cost and time of drug development. However, other new developments, many stemming from biotechnology, will help to improve the productivity of drug development. Such approaches as rational drug design, combinatorial chemistry, and in silico experimentation via computers have started to expedite the overall search for new drugs. New methods of data management complement those approaches. “It is often said that the next drug is buried in a pile of data,” says Shawn Green, founder of LabBook and BSML.org. “So we need informatic solutions that can transform data into knowledge — the most important asset in a life science company.”
The new tools and methods have already given researchers better understanding of the biochemical processes in cells and the ways in which they can synthesize compounds that will alter cellular behavior. “About 40 percent to 45 percent of all drugs in human clinical trials originated in biotechnology, up from 10 percent or less 10 years ago,” says William Haseltine, chairman and CEO of Human Genome Sciences. “The next decade will bring a rising tide of functional data from study of the human and other genomes that will aid in drug discovery,” adds Carl Feldbaum, president of the Biotechnology Industry Organization.
Increasing productivity means screening more samples in less time and with less labor. To accomplish this, manufacturers have developed high throughput screening (HTS) systems that range from semi automated work stations to fully automated robotic systems. “At the beginning of the 1990s only a few hundred proteins were well characterized,” recalls CAChe’s Purvis. “Now crystallographers are talking about high throughput crystallography — doing a structure in perhaps one day using robotics to work on crystallization conditions and the ability to express large quantities of proteins.”
HTS has universal utility. “Drug discovery and development involves looking at undefined substances, screening synthetic compounds for their drug potential, taking off from PCR, and other standard methods,” says Harald Andrulat, product manager of Eppendorf. “All ultimately have something to do with HTS.”
HTS products start out with liquid handling systems for the research laboratory, such as multichannel pipetters, 96-well plate fillers, and washers produced by Rainin Instruments and other firms. Eppendorf, meanwhile, recently introduced epMotion 5070, a work station aimed at scientists who need flexibility in liquid handling. Beyond that, says Jahns, “We want to look into solutions rather than supplying single products or pieces of equipment. “We aim to provide consumables and reagents with each piece of instrumentation for high throughput.”
At the other end of the HTS range suppliers provide work stations that fill, wash and rinse, and read fluorescence or other characteristics of a sample in addition to handling liquids. PerkinElmer is among the leaders in laboratory automation and HTS, while Applied Biosystems, Beckman Coulter, and Zymark offer sophisticated robotic systems that are even more versatile than work stations. Hamilton Company is developing high throughput proteomics work stations for applications such as MALDI TOF MS target spotting and protein crystallization. “We have been working with Data Centric Automation for a complete protein crystallization optimization work station,” adds Gary Engelhart, Hamilton’s national sales manager. Hamilton also offers flexible and sophisticated work stations, automating assays, and sample preparation during every phase of the drug discovery process.
Pharmaceutical companies have long tried to replace serendipity with logic in the effort to develop new drugs. In years past, rational drug design required medicinal chemists working at a lab bench to synthesize a relatively small number of compounds with the desired properties of a potential new drug. The step-by-step approach took many months or even years to complete.
The effort has produced results. “Our Tamiflu oral anti-influenza treatment was created through rational design by chemists at our partner Gilead,” says Lee Babiss, vice president of preclinical R&D at Roche. “But so far those results have tended to be one-off.” That situation is changing, however. “In the next five years,” Babiss predicts, “you’ll see a large number of compounds coming onto the market as a result of rational drug design.”
Current methods of rational drug design accelerate discovery by removing some of the randomness from the process. The methods involve the design and optimization of small organic molecules based on either information derived from a protein structure or a small collection of hits from high throughput screening. “You need two things: databases to hold all the information that comes out of your high throughput screening and various proprietary algorithms that allow you to dock compounds into the active sites you’re targeting,” explains Babiss.
Roche scientists use rational drug design to examine what happens at the molecular level when a drug binds with a receptor, thereby obtaining a three-dimensional picture of a binding site. They aim to develop drugs that bind optimally to a given receptor with greater selectivity, thus improving efficacy. “We are starting a program in metabolic diseases that involves lipid metabolism,” says Babiss. “It’s an example of our ability to do the in silico screening based on having a very deep database from screening data against the targets.”
Information companies also have a role in the process. “One of our real competencies has been rational drug design,” says Levine of Accelrys. “It’s important to get the information to the desktop without the need for written reports. Enabling people to access the science is almost as important as the science itself.”
Another approach to generating many compounds that may interact with a target is combinatorial chemistry, a method that creates every possible variant of a parent compound. Combinatorial chemistry plays a major role in constructing chemical libraries, a service offered by Cambridge Drug Discovery and PPD, among other companies. “We have a number of products that allow you to do virtual screening and database building,” says Levine of Accelrys. “Uniquely, we allow that information to be shared across products by chemists and biologists who don’t have to communicate individually. That helps companies to reengineer their culture to make work more efficient, getting everyone on the same page.”
Effective as they are individually, rational drug design and combinatorial chemistry work even better in partnership to shorten the drug discovery process. Companies such as Accelrys and Tripos have developed computer programs to help the design of synthetic molecules likely to have the desired biological properties, while minimizing the risks of such adverse effects as toxicity. “ADMET [absorption, distribution, metabolism, and excretion plus toxicity] is important,” says Purvis of CAChe. “We provide a number of tools to help the chemist predict those processes using simple rules such as Lipinsky’s rule of five, as well as allowing them to build their own custom systems. The software is universal, so that medicinal chemists can customize their models.”
Finding the right compounds once meant spending long hours searching the literature and making calls to colleagues in hopes of locating several compounds with specific characteristics. To reduce this time and increase the efficiency of locating possible drug candidates, companies have developed large databases and powerful search engines that allow researchers to enter the characteristics of a compound of interest and search for natural or synthetic compounds with similar properties. Accelrys, ChemNavigator, and Sigma–Aldrich provide scientists with the searchable chemical databases and also provide sources for the hits from these searches.
Databases have one disadvantage: an excess of information. “Chemical departments in drug discovery face an overload,” says Hans Johansson, CEO of Swedish company Personal Chemistry. “A lot of new hits have come into lead optimization through the use of high throughput screening. The overload, combined with methodology issues in which chemistry has not really been adapted to HTS and an almost global shortage of chemists, has made this a bottleneck, particularly for biotechnology companies that are moving into drug development.”
In response, “We’re looking at a new way to create, store, and share chemical knowledge,” Johansson continues. “We’re applying focused microwave energy to speed up chemical reactions, to increase yield, and to enable chemistries that would be difficult to get to go.” The technology, coherent synthesis, delivers highly reproducible results that are automatically stored and made available to any chemist in the organization. Personal Chemistry recently launched Emrys Knowledge Builder and Emrys Pathfinder. “We’re looking at a chemistry book of five thousand to 10 thousand pages in terms of proprietary knowledge,” says Johansson. “Applied throughout a large pharma’s chemistry department, it will rapidly exceed even that size and become a tremendously valuable asset for the whole organization. Scientists have already talked at conferences about up to 400 percent increases in productivity in terms of the lead optimization phase.”
Even laboratory notebooks are going the way of automation. “We are seeing a convergence of informatics and wet lab experimentation in the drug discovery process,” says Shawn Green of LabBook. Thus companies such as LabBook and ChemSW offer specialized versions of electronic laboratory notebooks to help scientists organize their information and experimental data.
“From a researcher’s perspective, paper based lab books remain the places to capture and share all key activities and assets within the drug discovery enterprise,” explains Green. “Electronic lab books need to overcome the hurdles established by paper records such as ease of use, portability, and legal and regulatory compliance — and in addition provide affordable functionality in information management.” That’s beginning to happen. Thus LabBook provides an electronic notebook — eLabBook — that integrates local data and documents with web based capabilities.
While pharmaceutical organizations are developing new drugs, the suppliers of instrumentation and reagents are busy supporting this industry with tools that are faster, more powerful, and more automated. To be effective, these new products must be designed with the end-user’s needs in mind. Working together, these industries offer the promise of more targeted and more effective drugs that will benefit all humankind.
Peter Gwynne is a freelance science writer based on Cape Cod, Massachusetts, U.S.A. Gary Heebner is a marketing consultant serving the scientific industry, based in Foristell, Missouri, U.S.A.
