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Drug design
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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.
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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 out 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
Unlike the historical method of drug discovery, by trial-and-error testing of chemical substances on cultured cells or animals, and matching the apparent effects to treatments, rational drug design begins with a knowledge of specific chemical responses in the body or target organism, and tailoring combinations of these to fit a treatment profile. Knowledge of the stability and reactivity of libraries of potential drug compounds is essential in Drug metabolism the predicted metabolic and toxicological outcomes and rational redesign of possible drug candidates. Several methods for predicting drug metabolism have been proposed in the scientific literature, and a recent example is SPORCalc. Due to 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 unequivocal 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 (chronic myelogenous leukemia and occasionally acute lymphocytic leukemia). 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.
The activity of a drug at its binding site is one part of the design. Another to take into account is the molecule's druglikeness, which summarizes the necessary physical properties for effective absorption. One way of estimating druglikeness is Lipinski's Rule of Five.
Computer-assisted drug design
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.
Examples of designed drugs
See also
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