Rational drug design

Drug targets[ edit ] A biomolecular target most commonly a protein or nucleic acid is a key molecule involved in a particular metabolic or signaling pathway that is associated with a specific disease condition or pathology or to the infectivity or survival of a microbial pathogen. Potential drug targets are not necessarily disease causing but must by definition be disease modifying. Small molecules for example receptor agonistsantagonistsinverse agonistsor modulators ; enzyme activators or inhibitors ; or ion channel openers or blockers [11] will be designed that are complementary to the binding site of target.

Rational drug design

The Pharmaceutical Journal 2 JUL Structure-based drug design is now a common method used by thepharmaceutical industry to identify a lead compound and take it forwardfor further development.

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. 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. Generally, the rational development Rational drug design 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.

Rational drug design target then has to be fully characterised and, finally, a molecule must be designed that binds to it.

Rational drug design

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. 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.

Proteomics 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.

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, 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.

DNA 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.

One enzyme that has had a great deal of attention over the years is angiotensin-converting enzyme ACEwhich 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.

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: 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. 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.

Conclusion 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.Dec 25,  · In this article, current knowledge of drug design is reviewed and an approach of rational drug design is presented.

The process of drug development is challenging, expensive, and time consuming, although this process has been accelerated due to the development of computational tools and methodologies. Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target.

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. Conclusion A drug discovery team is often multidisciplinary. Rational drug design can be broadly divided into two categories: (A) Development of small molecules with desired properties for targets, biomolecules (proteins or nucleic acids), whose func-.

The three major steps of rational drug design are: Step 1. Identify a receptor or enzyme that is of relevance.

Rational drug design

Step 2. Characterize the structure and function of this receptor or enzyme. Step 3. Design a drug molecule that interacts with the receptor or enzyme in a therapeutically beneficial way. An example of a drug that was designed in this manner .

Dec 25,  · Hence, rational drug design would require a multidisciplinary approach. In this regard, incorporation of gene expression technology and bioinformatics tools would be indispensable in the structure based drug design.

What is Rational Drug Design? (with pictures)