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Target validation normally requires the determination that the target is expressed in the disease-relevant cells/tissues, [6] it can be directly modulated by a drug or drug-like molecule with adequate potency in biochemical assay, [7] and that target modulation in cell and/or animal models ameliorates the relevant disease phenotype. [8]
Forward and reverse pharmacology approaches in drug discovery. In the field of drug discovery, reverse pharmacology [1] [2] [3] also known as target-based drug discovery (TDD), [4] a hypothesis is first made that modulation of the activity of a specific protein target thought to be disease modifying will have beneficial therapeutic effects.
Biomarkers are usually required to aid the selection of patients who will likely respond to a given targeted therapy. [6] Co-targeted therapy involves the use of one or more therapeutics aimed at multiple targets, for example PI3K and MEK, in an attempt to generate a synergistic response [5] and prevent the development of drug resistance. [7] [8]
Another method for drug discovery is de novo drug design, in which a prediction is made of the sorts of chemicals that might (e.g.) fit into an active site of the target enzyme. For example, virtual screening and computer-aided drug design are often used to identify new chemical moieties that may interact with a target protein.
This approach is known as "reverse pharmacology" or "target based drug discovery" (TDD). [5] However recent statistical analysis reveals that a disproportionate number of first-in-class drugs with novel mechanisms of action come from phenotypic screening [ 6 ] which has led to a resurgence of interest in this method.
The term "biological target" is frequently used in pharmaceutical research to describe the native protein in the body whose activity is modified by a drug resulting in a specific effect, which may be a desirable therapeutic effect or an unwanted adverse effect. In this context, the biological target is often referred to as a drug target.
The phrase "drug design" is similar to ligand design (i.e., design of a molecule that will bind tightly to its target). [6] Although design techniques for prediction of binding affinity are reasonably successful, there are many other properties, such as bioavailability, metabolic half-life, and side effects, that first must be optimized before a ligand can become a safe and effictive drug.
Individual differences in drug metabolism and response can be partially explained by epigenetic changes. [7] [8] Epigenetic changes in genes that encode drug targets, enzymes, or transport proteins that affect the body's ability to absorb, metabolize, distribute and excrete substances that are foreign to the body (Xenobiotics) can result in changes in one's toxicity levels and drug response.