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DRUG DESIGNINGING
- A CHALLENGE TO SCIENTISTS
- A CHALLENGE TO SCIENTISTS
Cancer is one of the most widespread and feared diseases in the Western world is today feared largely because it is known to be difficult to cure. The main reason for this difficulty is that cancer results from the uncontrolled multiplication of subtly modified normal human cells. One of the main methods of modern cancer treatment is drug therapy (chemotherapy). The majority of drugs used for the treatment of cancer today are cytotoxic (cell-killing) drugs that work by interfering in some way with the operation of the cell's DNA. A major challenge is to design new drugs that will be more selective for cancer cells, and thus have lesser side effects. Initially the specificity of drugs was worked out simply by testing on animals, but now it is possible to use our knowledge of cancer cell biology to actively design drugs to be more specific. However, animal tests still need to be carried out at some point. As with any pharmaceutical, new anticancer drugs are developed in a three-step process.[25](Mandal et.al., 2009)
Step 1 - Initial discovery
A wide range of compounds, both natural and synthetic, are tested in high-capacity screens to discover molecules with useful properties.
Step 2 - Molecular modification of a known compound
A molecule that shows suitable properties is chemically altered to give it the best combination of properties to make the most effective anti-cancer drug.
Step 3 - Development into a useful pharmaceutical
Because the above process is very time-consuming and expensive, the new discovery is usually patented at this time so that the discoverers can eventually recover some of these costs. The most effective route for synthesizing the molecule is then worked out. A long process of advanced testing is then begun, ending up with tests on patients in specialized hospitals. If the results are favorable, the drug is then able to be released for use.
The process of drug development is very long and involved, with maybe only one in ten thousand of the molecules originally tested finally being clinically used.
[Narang and Desai, 2009]
Conventional anticancer drug development efforts focused on cytostatic or cytotoxic compounds that caused tumor regression. These paradigms have been expanded to include target pre-selection for the discovery of molecularly Anticancer Drug Development
targeted therapeutic agents. In addition, drug types such as immunomodulators, chemoprotectants, MDR-reversing agents, photosensitizers, and hormonal drugs present an increasing arsenal with unique drug development needs and possibilities of drug combinations to maximize therapeutic outcome. Furthermore, the use of molecular biology technologies such as pharmacogenetics and metabolomics with cytotoxic agents can help control drug toxicity and better predict drug response. Prudent application of these opportunities is significantly influencing the preclinical and clinical development of novel anticancer therapeutics. The new drug discovery and development process is a systematic approach to identify potential new drug candidates and their evaluation for drug-like properties. Although the discovery and development of anticancer compounds follow the same process as any other new molecular entities (NMEs), they have several unique aspects that impact their development paradigms. The new drug development process typically involves the following stages, not necessarily in a sequential manner:
1. Acquisition of potential compounds:
This could be achieved by chemical synthesis or by extraction from natural resources. This stage includes the development of analytical methods to confirm identity and purity of the compound, and its stability under real-life and stressed storage conditions. Physicochemical properties of the compound are identified, such as the solid-state form (polymorphism, hydrates, and solvates), melting point, solubility, and stability. Synthesis of the molecule is scaled up as the compound progresses in the development pathway. A formulation suitable for human administration and commercialization is identified and scaled-up.(Narang and Desai,2009)
2. Drug screening and preclinical pharmacology:
This involves ‘‘paper chemistry’’ whereby the drug structure is compared to those of existing compounds in the databases to identify potential activity, toxicities, degradation pathways, metabolic routes, etc. A preliminary screening in cell culture models is carried out to identify the extent and specificity of its antitumor activity. This is followed by the evaluation of efficacy and
toxicity in animal models.(Narang and Desai,2009)
3. Clinical development:
Clinical development of a drug candidate involves testing in human volunteers to identify the toxicities and the maximum tolerated dose (MTD) in phase I clinical trials. Subsequently, phase II studies are carried out in patients of selected tumor type to quantify efficacy and confirm dosage. Subsequently, larger phase III studies are aimed at head-to-head comparison of theNCE with the then-best-available therapy.(Narand and Desai,2009)
FURTHER MORE ON DRUG DESIGN.......
Reference: http://www.discoverymedicine.com/Jennifer-Arrondeau/2010/10/26/development-of-anti-cancer-drugs/