What is drug design ? How drug can be designed ?

rational drug design structure based drug design computer assisted drug design 3D- QSAR

Examples of drug design Zanamivir

References

Drug design is the approach of finding drugs by design, based on their biological targets. Typically a drug target is a key molecule involved in a particular metabolic or signalling pathway that is specific to a disease condition or pathology, or to the infectivity or survival of a microbial pathogen.

Some approaches attempt to stop the functioning of the pathway in the diseased state by causing a key molecule to stop functioning.

Drugs may be designed that bind to the active region and inhibit this key molecule. However these drugs would also have to be designed in such a way as not to affect any other important molecules that may be similar in appearance to the key molecules.

Sequence homologies are often used to identify such risks.

Other approaches may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state.

The structure of the drug molecule that can specifically interact with the biomolecules can be modeled using computational tools. These tools can allow a drug molecule to be constructed within the biomolecule using knowledge of its structure and the nature of its active site.

Construction of the drug molecule can be made inside or outside in depending on whether the core or the R-groups are chosen first. However many of these approaches are plagued by the practical problems of chemical synthesis.

Newer approaches have also suggested the use of drug molecules that are large and proteinaceous in nature rather than as small molecules.

There have also been suggestions to make these using mRNA. Gene silencing may also have therapeutical applications.

Rational drug design Structure based drug design Computer assisted drug design 3D- QSAR

Unlike the historical method of drug discovery, rational drug design begins with a knowledge of specific chemical responses in the body or target organism, and making combinations of these to fit a treatment profile.

Because of the complexity of the drug design process two terms of interest are still serendipity and bounded rationality. Those challenges are caused by the large chemical space describing potential new drugs without side-effects.

A particular example of rational drug design involves the use of three-dimensional information about biomolecules obtained from such techniques as x-ray crystallography and NMR spectroscopy. This approach to drug discovery is sometimes referred to as structure-based drug design.

The first example of the application of structure-based drug design leading to an approved drug is the carbonic anhydrase inhibitor dorzolamide which was approved in 1995

Another important case study in rational drug design is imatinib, a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein that is characteristic for Philadelphia chromosome-positive leukemias (CML and ALL).

Imatinib is substantially different from previous drugs for cancer as most agents of chemotherapy simply target rapidly dividing cells, not differentiating between cancer cells and other tissues.

In structure-based drug design, the three-dimensional structure of a drug target interacting with small molecules is used to guide drug discovery.

Structure-based drug design represents the idea that you can see exactly how your molecule interacts with its target protein.

Structure-based drug design was equated with de novo design or building a molecule from the ground up. The active site of the protein was a space to be filled with a molecule that complemented it in terms of shape, charge, and other binding components.

In structure-based drug design, scientists In structure-based drug design, scientists use detailed knowledge of the active sites use detailed knowledge of the active sites of protein targets associated with particular of protein targets associated with particular diseases to design synthetic compounds diseases to design synthetic compounds that fight the disease. that fight the disease.

The active site of an enzyme is the area into The active site of an enzyme is the area into which a chemical or biological molecule fits which a chemical or biological molecule fits to initiate a biochemical reaction. to initiate a biochemical reaction.

Structure-based drug design aims to create Structure-based drug design aims to create a molecule that will bind to the active site of a molecule that will bind to the active site of a targeted enzyme, thereby preventing the a targeted enzyme, thereby preventing the normal chemical reaction and ultimately normal chemical reaction and ultimately halting the progression of the disease.halting the progression of the disease.

Crystallography, is the scientific discipline that is at the center of structure-based drug design. Crystals are solid substances with symmetrically arranged molecules.

Obtaining large, well-ordered crystals is essential for a crystallographer to be able to analyze the three-dimensional molecular structure and active site of the proteins that control cellular biology.

BioCryst's scientists use X-ray crystallography throughout the process of designing and optimizing potential drugs.

First, they use crystallography to determine the structure of their target proteins. This structure is used to design potential compounds that will fit the active site of the target.

Scientists then use crystallography to study how compounds bind with the active site of the target protein. Using information gained through crystallography, researchers refine the compounds to improve their performance

Traditionally, scientists identify new drugs either by fiddling with existing drugs or by testing thousands of compounds in a laboratory. If you think of the target molecule as a lock, this approach is rather like trying to design a key perfectly shaped to the lock.

Using a structure-based strategy, researchers have an initial advantage. They start with a computerized model of the detailed, three-dimensional structure of the lock and of its key.

Then scientists try to design a molecule that will plug up the lock to keep out the substrate key.

Knowing the exact three-dimensional shape of the lock, scientists can discard any of the metal scraps (small molecules) that are not the right size or shape to fit the lock. They might even be able to design a small molecule to fit the lock precisely. Such a molecule may be a starting point for pharmaceutical researchers who are designing a drug to treat HIV infection

Computer-assisted drug design uses computational chemistry to discover, enhance, or study drugs and related biologically active molecules.

Methods used can include simple molecular modeling, using molecular mechanics, molecular dynamics, semi-empirical quantum chemistry methods, ab initio quantum chemistry methods and density functional theory.

The purpose is to reduce the number of targets for a good drug that have to be subjected to expensive and time-consuming synthesis and trialling.

Quantitative Structure-Activity Relationship(QSAR) studies are widely used in drug design, in particular, for hit-to-lead and lead optimizations.

Quantitative structure-activity relationship (QSAR) is the process by which chemical structure is quantitatively correlated with a well defined process, such as biological activity or chemical reactivity.

For example, biological activity can be expressed quantitatively as in the concentration of a substance required to give a certain biological response.

Additionally, when physicochemical properties or structures are expressed by numbers, one can form a mathematical relationship, or quantitative structure-activity relationship, between the two. The mathematical expression can then be used to predict the biological response of other chemical structures.

QSAR's most general mathematical form is:Activity = f(physiochemical properties and/or structural

properties)

Cimetidine, the prototypical H2-receptor antagonist from which the later members of the class were developed

Dorzolamide, a carbonic anhydrase inhibitor used to treat glaucoma

Many of the atypical antipsychotics Selective COX-2 inhibitor NSAIDs SSRIs (selective serotonin reuptake inhibitors), a

class of antidepressants Zanamivir, an antiviral drug Enfuvirtide, a peptide HIV entry inhibitor Probenecid Nonbenzodiazepines like Zolpidem and Zopiclone

Relenza (zanamivir), an anti-viral drug, for persons aged 7 years and older for the treatment of uncomplicated influenza illness. This product is approved to treat type A and B influenza, the two types most responsible for flu epidemics.

The drug works by destroying an enzyme, neuraminidase, on the surface of the virus, essential for the multiplication and spread of influenza.  Relenza is not a vaccine.

Neuraminidase inhibitorsNeuraminidase inhibitorsZanamivir was the first of a new generation of drugs known as neuraminidase inhibitors, capable of treating or preventing infection from the influenza virus.

Neuraminidase is essential for the replication of all influenza viruses.  It is an enzyme which allows new viruses to be released from the infected lung cells, further extending the infection.  Neuraminidase inhibitors block this activity, preventing the release and spread of new viruses.

Clinical studies showed that for the drug to be effective, patients needed to start treatment within two days of the onset of symptoms.

The drug seemed to be less effective in patients whose symptoms weren't severe or didn't include a fever.

Relenza is approved for preventive use, to decrease the risk of developing influenza illness, for persons aged 5 and older. Relenza has not been proven effective for prevention of influenza in nursing home patients.

http://en.wikipedia.org/wiki/Drug_design http://www.proxychem.com/sbdd.html http://www.biocryst.com/

structure_baseddrugdesign.htm http://pubs.acs.org/cen/coverstory/

7923/7923drugdesign.html http://www.netsci.org/Science/Compchem/

feature12.html http://www.fda.gov/cder/news/relenza/

default.htm http://www.chemosoft.com/modules/

drug_design/qsar/