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Drugs are generally small organic molecules (< 500 Da) (Lipinski, Lombardo et al. 2001) which agonizes, antagonizes, or inhibits a target molecule in a biological pathway producing a physiological response. Most drugs targets are proteins, and the function of the target proteins vary from receptors, to enzymes, to ion channels. (Drews 2000)
The process of drug discovery and development is the identification, or creation, of a bioactive compound and its subsequent modification in to a drug, balancing both its potency and safety. (Barril, Brough et al. 2005; Mitscher and Dutta 2006) To discover and develop a new drug can take upwards of 10 to 15 years. (Lipsky and Sharp 2001; Aronovitz 2006) The path of drug discovery and development has four stages. (Baxter and Lockey 2001; Bleicher, Bohm et al. 2003; Nwaka and Ridley 2003; Deprez-Poulain and Deprez 2004; Aronovitz 2006; Keseru and Makara 2006; Mitscher and Dutta 2006)
The first stage in drug discovery is target selection. (Baxter and Lockey 2001; Bleicher, Bohm et al. 2003; Nwaka and Ridley 2003; Deprez-Poulain and Deprez 2004; Aronovitz 2006; Keseru and Makara 2006; Mitscher and Dutta 2006) Target selection starts with the basic science research required to understand the pathology of the disease to determine possible pharmacological interventions. Once a target is selected, the data obtained on the target determines how drug discovery will proceed. If there is an experimental structure of the target, then structure based drug discovery (SBDD) is used, where the discovery process is governed by the shape and chemistry of the target. In other cases, if the structure of the target is unknown, but the structure of a ligand is known (Andricopulo, Salum et al. 2009), then ligand based drug discovery is used, where drug discovery proceeds is based on modifying the structure and chemistry of a known ligand.
The goal of the second stage of drug discovery is hit generation. Hits are compounds that are “active” against the target. (Baxter and Lockey 2001; Bleicher, Bohm et al. 2003) Hits are identified through methods such as high throughput screening (HTS) (Macarron 2006), fragrant screening (Fischer and Hubbard 2009), or virtual screening (Shoichet 2004). In these methods, researchers screen chemical libraries to identify “active” compounds. The activity of a compound is based on some predetermined threshold of potency, like binding or inhibition concentrations. (Mitscher and Dutta 2006) A common metric for classifying a compound as a hit is that the compound has activity at low micromolar concentration. (Baxter and Lockey 2001)
In the third stage of drug discovery, researchers develop hits into lead compounds and then into candidate compounds for human trails. Lead compounds are chemically modified hits with increased potency, usually in the high (>100) nanomolar range. (Baxter and Lockey 2001; Bleicher, Bohm et al. 2003) The lead compound’s absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) are tested at this stage and the lead is modified to improve safety. (Hodgson 2001) A lead compound becomes a candidate compound for human trial when it achieves safety and potency requirements. (Baxter and Lockey 2001; Bleicher, Bohm et al. 2003)
The final stage of drug discovery and development is the process of the candidate compound becoming a drug though clinical trials. (Lipsky and Sharp 2001; Aronovitz 2006) Clinical trials in the United States have three stages. The first stage determines the drug’s safety in healthy adults. The second proves potency of the drug in a small study with hundreds of subjects. The third stage test safety and potency of the drug in a large study with thousands of subjects. If a drug passes all three stages, it then goes to market, during which its potency and safety is continuously monitored. (Lipsky and Sharp 2001; Aronovitz 2006)