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Rational drug design — identifying and characterising a target

Structure-based drug design is now a common method used by thepharmaceutical industry to identify a lead compound and take it forwardfor further development. Adam Todd, Roz Anderson and Paul W.Groundwater describe the methods used to identify and characterise atarget for structured drug design and illustrate how pharmacists canplay an important role in this process

by Adam Todd, Roz Anderson and Paul W. Groundwater

Structure-based drug design is now a common method used by the pharmaceutical industry to identify a lead compound and take it forward for further development.

Adam Todd, Roz Anderson and Paul W. Groundwater describe the methods used to identify and characterise a target for structured drug design and illustrate how pharmacists can play an important role in this process

See also Rational drug design — designing a molecule that binds to a target


Many drugs available today were discovered by chance. Such serendipitous drug discovery has led to many drugs used commonly in pharmacy, such as glyceryl trinitrate and warfarin.

Although serendipity has had a role to play in the pharmaceutical industry over the years, current drug discovery is an extraordinarily complicated, expensive and time-consuming process, with strategies involving screening natural products, mimicking biological substrates (and metabolites), and the use of  structure-based drug design.

Generally, the rational development of a new drug follows a three-step process. Initially, a target, such as a receptor or enzyme, has to be identified relating to a particular disease state. This target then has to be fully characterised and, finally, a molecule must be designed that binds to it.

This last part of the process can take years since, even with good structural information, it is difficult to design a drug with the desired pharmacological activity that will bind specifically to a given target.  

Pharmacists can be an integral part of the drug design team because they have an almost unique understanding and knowledge base in the field of drug discovery, ranging from medicinal chemistry to pharmacokinetics and drug metabolism.

Temozolomide and atracurium, both highly successful drugs on the market today, are examples of drugs discovered by research teams led by pharmacists.1,2


Identifying a target

Over the years, the understanding behind the molecular mechanisms of disease has significantly increased and this has allowed the identification of many biological macromolecules implicated in disease, many of which are involved in specific cellular-signalling pathways.

Often, in disease states, there is a disruption or imbalance in a signalling pathway, for example, the enzyme cyclo-oxygenase (COX) is up-regulated in inflammatory disorders, leading to the production of pro-inflammatory prostaglandins.

One approach in drug design is to target and restore the normal signalling pathway by inhibiting the dysfunctional biomolecules, for example, non-steroidal anti-inflammatory drugs inhibit COX, which inhibits the synthesis of prostaglandins, thus alleviating inflammation.



One technique that can be used to identify the biological macromolecules implicated in disease is proteomics, which can be defined as the qualitative and quantitative comparison of proteomes under different conditions to unravel biological processes.3

The proteome is the total number of proteins expressed by a cell and can consist of more than a million proteins.

Normal healthy cells can be compared with cells from a particular disease state (eg, cancer) and proteins either up-regulated or down-regulated can be identified using proteomics, which involves the use of the hyphenated analytical technique liquid chromatography–mass spectroscopy (LC–MS).

This is an extremely powerful technique and can play a significant role in the identification of impaired signalling pathways in disease pathology. Once a target has been found to play a role in disease pathology, the next step is to characterise it.


The protein databank

The recent advances in nuclear magnetic resonance spectroscopy and X-ray crystallography have allowed characterisation of numerous biological macromolecules, such as receptors, nucleic acids and enzymes.

X-ray crystallography is used to generate the structure of a molecule by the diffraction of X-rays through a crystal. The analysis of the diffraction patterns gives an electron density map from which the structure of a molecule can be determined.

Once characterised, the structures of these molecules are stored in a large database, known as the protein databank,4 which currently contains the structures of more than 52,000 molecules. The structures provided by this database are in the public domain and are easily accessible through the internet.

Once the structures have been characterised and deposited into the protein databank, they can be used as a starting point for rational drug design.



Over the years, nucleic acids, enzymes and receptors have all been identified as targets for various different diseases and this has led to the development of drug molecules targeting these specific biological macromolecules. Indeed, most drugs on the market today act on either a receptor, DNA or an enzyme.

For example, the anthracycline antibiotic, doxorubicin, intercalates with DNA and inhibits cell replication by interfering with transcription.

Doxorubicin can be used as part of a chemotherapeutic regimen to treat acute leukaemias, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and some solid tumours.5


Enzyme inhibitors

Enzyme inhibitors account for many of the drugs on today’s market and cover many different therapeutic areas. One enzyme that has had a great deal of attention over the years is angiotensin-converting enzyme (ACE), which is a key enzyme in the renin-angiotensin-aldosterone system and converts angiotensin-I into angiotensin-II. Angiotensin-II causes blood vessels to constrict, resulting in an increase in blood pressure.

The role ACE plays in the renin-angiotensin-aldosterone system makes it an ideal drug target for the treatment of essential hypertension and renal disease. Captopril, the first orally active ACE inhibitor, was developed by Squibb (now Bristol-Myers Squibb) in the early ’80s7 and was found to offer a novel therapeutic route for the treatment of essential hypertension.

The success of captopril allowed other drug companies to develop ACE inhibitors and, currently, there are more than 10 ACE inhibitors on the market licensed for the treatment of hypertension.


Receptor agonists and antagonists

Receptor agonists or antagonists have also had an important part to play in the pharmaceutical industry and one of the most studied receptors in drug design is the beta adrenoceptor. The beta adrenoceptor has three different subtypes: beta-1, beta-2 and beta-3.

Each of the beta adrenoceptor subtypes has different functions, for example, activation of the beta-1 adrenoceptor can increase heart rate by increasing cardiac output, while activation of the beta-2 adrenoceptor can cause smooth muscle relaxation in the bronchi. Less is known about the beta-3 adrenoceptor, but it is thought to play a role in the breakdown of fat in adipose tissue.8

The pharmaceutical industry has taken advantage of the different functions of each subtype of beta adrenoceptor through selective targeting.

For example, the development of the beta-2 adrenoceptor agonist salbutamol has had a significant impact in the management of asthma, while the beta-1 adrenoceptor antagonist atenolol is still successfully used in the management of angina and hypertension.


Rational drug design

The identification and characterisation of a biological macromolecule implicated in disease pathology acts as a starting point for rational drug design. Rational drug design can then be used to design a drug molecule that restores the balance of the signalling pathway by inhibiting or stimulating the biological target as appropriate.  



A drug discovery team is often multidisciplinary. Pharmacists offer a wide range of skills relating to the discovery of drugs and often provide an essential link between the chemists and biologists in the drug discovery team.

Proteomics and X-ray crystallography have allowed the identification and characterisation of many therapeutic targets — the first step in the long and complicated process of drug discovery. The next stage in the process is to design a molecule that binds to a biological target. This can be notoriously difficult because it is important for a new drug to bind selectively to its target.

If a drug molecule is not selective and binds to other biological macromolecules in the body, undesirable adverse side effects may result. A well validated target and good structural information are thus vitally important when developing a new drug molecule.


Adam Todd, MRPharmS, is senior lecturer in pharmacy practice, and Roz Anderson is professor of pharmaceutical chemistry and MPharm programme leader, both at Sunderland Pharmacy School, University of Sunderland.

Paul W. Groundwater is professor of medicinal chemistry at the faculty of pharmacy at the University of Sydney, Australia



1.    Newlands ES, Stevens MFG, Wedge SR, Wheelhouse RT, Brock C. Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treatment Review 1997;23:35–61.

2.    Stenlake JB, Waigh RD, Urwin J, Dewar GH, Coker GG. Atracurium: conception and inception. British Journal of Anaesthesia 1983;55:3S–10S.

3.    Vollmer M, Nägele E, Hörth P. Differential proteome analysis: two-dimensional nano-LC/MS of E. coli proteome grown on different carbon sources. Journal of Biomolecular Technology  2003;21:289–307.

4.    Protein Data Bank. Available at (accessed on 19 June 2009).

5.    British National Formulary 55, March 2008. p454–5.

6.    Cirilli M, Bachechi F, Ughetto G, Colonna FP, Capobianco M. Interactions between morpholinyl anthracyclines and DNA: the crystal structure of a morpholino doxorubicin bound to d(CGTACG). Journal of Molecular Biology 1993:230;878–89.

7.    Smith CG, Vane JR. The discovery of captopril. The FASEB Journal 2003;17:788–9.

8.    Ferrer-Lorente R, Cabot C, Fernandez-Lopez JA, Alemany M. Combined effects of oleoyl-estrone and a beta3-adrenergic agonist (CL316,243) on lipid stores of diet-induced overweight male Wister rats. Life Sciences 2005;77:2051–8.

Citation: The Pharmaceutical Journal URI: 10969751

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Supplementary images

  • Temozolomide molecule: temozolomide is an example of a drug discovered by research teams led by pharmacists (Dr Tim Evans/Science Photo Library)

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