5 min readLead Discovery: Laying Foundations for Next-generation Drug Design

Drug discovery is the core focus of the pharmaceutical research arena and several organizations are working towards developing new drug molecules. Tremendous developments in the fields of genetics, genomics, molecular and cell biology, and proteomics have helped modernise the drug discovery process, resulting in the design of many disease-specific drugs. Extensive technological upgradation has also shortened the time frame for innovative drug design.

Researchers focused on drug discovery have made remarkable progress in understanding the molecular mechanisms of disease. This has been possible with the advent of the human genome project, which is expected to lead to identification of more than 10,000 drug targets. These will require evaluation against the compound libraries to compare the gene sequence.

Emerging Trends in the Drug Discovery Process
Frost & Sullivan’s analysis shows that the drug discovery market in Western Europe was worth $17 billion in 2007. It is expected to grow at a compound annual growth rate 13%, hitting $42 billion by 2014. In the past 25 years, the pharmaceutical industry has invested heavily in high-throughput technologies to decrease costs and provide access to new targets, accelerating the identification of active compounds. However, there is a disparity between levels of R&D investment and the development of innovative new drugs.

Due to the near-term loss of patent protection for many drug products and generic competition, there is pressure to develop new lead compounds. One way of tackling this has been through patent extensions. There is also pressure to reduce the time spent in drug discovery and to improve cost-effectiveness. Indeed, over the last couple of years the US FDA has noted a fall in the number of new molecules entering the regulatory pipeline. While outsourcing is touted as a potential solution, many companies fear that this may lead to losses in control, intellectual property and confidentiality. To this are added worries about regulatory compliance, political stability and the reliability of contractors when dealing with offshore Contract Research Organisations (CROs).

Pharmaceutical companies all aim to develop novel therapeutic agents towards specific diseases. With the help of the three-dimensional structure of the target-ligand complex, it is possible to design novel therapeutic compounds. It is however essential to have knowledge about the molecular mechanism of the disease and the biological structure of the target to accomplish this task. Apart from these techniques, combinatorial techniques, high-throughput screening and automated methods are promising to screen thousands of compounds at a given time.

Frost & Sullivan believes that biomarkers are the future trend in drug discovery. The development of technology platforms for measuring the biomarkers that are indicators of disease stages or compound toxicity is a promising avenue for streamlining the entire drug discovery process. In addition, fragment based drug discovery and fragment based screening, together with label free technology, high content screening (HCS) and predictive drug discovery with the use of in silico platforms will drive the drug discovery market towards generating revenues of $42 billion by 2014.

Tremendous research in biomarker discovery and clinical validation has been the chief driver for the drug discovery market, especially in the oncology market. Biomarkers have an increased responsibility in cancer testing, with tremendous application in drug efficacy testing.

High Throughput Screening: Enhancing the Drug Discovery Process
A majority of pharmaceutical and biotechnology companies prefer high throughput screening (HTS) technologies. HTS is a scientific process that is used to assess given samples of a compound molecule in a short span of time. This process is frequently used in drug discovery procedures. There have been a number of recent technological upgrades in the field of HTS, such as the inclusion of modern robotics, liquid handling devices and the incorporation of software. These tools minimize the time taken for reactions. The results of the HTS process are crucial, as they help in the first stage of discovery and subsequent drug design. HTS also helps in understanding the biomolecular pathways and biochemical processes involved in the synthesis of a particular drug.

HTS is being influenced by various technological trends such as cell-based assays, high content screening, robotics and automation.

The technical factors driving the HTS market are:

  • Constant developments in genomics and proteomics that have led to the development of new target molecules. The advantage of genomics lies in its specificity and the ability to develop customized drugs.
  • The success of bioinformatics, which has led to wide acceptance in HTS. Bioinformatics helps in predicting the biological nature of the molecule.
  • The use of combinatorial chemistry and microfluidics, which has had a great impact on the HTS market. Within the HTS process there has been gradual transformation from 96 well plates to 384 well plate formats. This has succeeded in reducing the reagents’ cost.
Apart from the factors listed above, two other factors driving the market include:

The Demand for Newer Drugs
The increase in the number of diseases and disorders means that pharmaceutical companies are constantly innovating newer molecules. In spite of the high demand for new drugs though, cost is a major issue that must be considered. End users demand effective as well as economical drugs. The revenues generated from the success of their past drug launches can aid in the R&D projects for established market participants, however new market entrants find financing R&D a significant challenge. Governments are showing a keen interest in the field of molecular biology and biotechnology though, and Frost & Sullivan anticipates that they will increasingly become potential sources of support.

Genomics and Proteomics
New target molecules are being identified as potential drug targets with the help of proteomics and genomics. This also helps in designing customized drugs for specific diseases. The therapeutic options are therefore expanded and drugs are formulated at the genetic level.

The various factors that pose as restraint to the market include:

Time Consumption
Drug discovery is a time consuming process and is further lengthened by the complications met at every step of the process. The reactions that take place during the process are sensitive and care must be taken to monitor them properly.

Governments and regulatory bodies also have stringent procedures for drug discovery that need to be adhered to. These are inevitably time consuming, and when errors are encountered the entire process might have to be called off. This is a great loss in time and resources.

High Costs
HTS instruments are expensive and small laboratories can typically not afford them. This is a limiting factor, which inhibits the number of users taking up HTS in their laboratories. Although the instruments are a one time investment, many smaller organizations are hesitant to invest such huge amounts. The major investment in terms of time is also a restraining factor that compels many companies to outsource their R&D to private laboratories.

Lack of Specificity
The process of drug discovery and HTS is time consuming, without certainty in the results. During the process of HTS, many hundreds or even thousands of screenings are done. Out of these, only one or two are converted into potential leads. At times, even the isolation of one or two leads is not possible, leading to no results at the end of the entire HTS process. Until the time of the final results, nothing can be predicted, as the number of probable leads cannot be estimated until the end of the reaction. Since reactions are highly sensitive, even a slight change in the temperature or the nature of the reagents can adversely affect it.

Traditionally, high throughput screening has not delivered on its promise of increasing the numbers and quality of new drugs entering clinical trials. The lack of success is due in part to the complexity and the relatively large size of the compounds routinely being screened. Frost & Sullivan believes this issue can be addressed by fragment based drug discovery (FBDD), an alternative approach, which uses very small, low molecular weight, drug fragments as its starting points. These fragments have the potential to keep the overall complexity and molecular weight of each drug candidate low, which is a key factor in successful drug development.

Astex’s Pyramid platform integrates biophysical techniques such as X-ray crystallography, nuclear magnetic resonance spectroscopy and isothermal calorimetry with fragment library design and a range of computational methodologies into a proprietary approach for fragment-based drug discovery.

Conclusion
Developing safe and effective new drugs is a time consuming and expensive process. While the cost of developing new drugs is increasing rapidly, withdrawals of drugs from the marketplace due to adverse drug reactions and/or toxicity is increasing concurrently. Better target selection and the appropriate use of predictive technologies are among the approaches currently being pioneered for an improvement in the discovery of new drug candidates. The recent advent of high throughput in silico (computer software) and in vitro (cell culture) screenings have addressed some, but not all, of these challenges by providing an efficient and effective way for developing safer and better drugs.

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