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Small molecule-based drug discovery and development: An introduction
Dr. James Wen

Small molecule-based drug is referring to a biologically active chemical compound that its molecular weight is less than 500 in general (exceptions do exist). Now-days, discovering a small molecule-based drug is not a trivial endeavor. It is not only time consuming, but also costly. According to Chemical & Engineering News, on average, it takes about 14 years (including first 3 years of launch) to develop a drug, and the price tag for such development is about $800 million (500 million R&D, 300 million marketing).

There are several sequential steps that a typical drug discovery and development process has to go through.

First, choose of validated drug targets (usually biologically active proteins). At this first stage, one needs to determine what diseases the new drug will be targeting on, and what biological proteins are involved in those disease states.

Second, compound screenings. Once the drug targets are determined, a set of biological assays are then set up to identify any chemical compounds that can bind to the biologically active proteins with high affinity. Those tight binders are in general called “drug leads”.

Third, leads optimization. The drug leads identified from compound screenings are usually not drug like. They need to be further optimized using an iterative chemical modification process to become more drug like, in terms of biological potency and physical properties, such as solubility, actual amount of drug delivered to the target tissue, and selectivity for the chosen proteins over closely related proteins, etc.

Fourth, animal testing. The best drug candidate identified from leads optimization is taken into safety and toxicology testing to determine whether it is safe enough to go into humans at a dose where efficacy may be expected. At this stage, mouse, dog and monkey are usual suspects for such testing.

Fifth, clinical trials. Once a drug candidate passed animal testing, it is then tested in humans in clinical trials. The trials are conducted in three phases. In phase one trials, the compound is dosed to healthy volunteers. If the compound is proven to be safe at the proposed doses, then it is moved to the phase two trials. During phase two trials, patients with the disease are given the dosed compound. Any signs of efficacy in patients with such treatment are closely monitored and analyzed. If there are signs that the compound is active enough, it can then go into phase three trials, which tend to be very big and expensive. There are several crucial questions need to be answered during the phase three trials. For example, how well does the drug work? What are its side effects at the proposed efficacy doses? What kind of a dosing schedule is optimal? How does it interact, favorably or unfavorably, with other drugs for the same or related conditions, etc.

Sixth, FDA approval. Finally, the drug candidate that has successfully passed human clinical trials needs to get approval from FDA before its launch in the market place. FDA shall review all clinical trial data related to the drug candidate, and make judicial decision on the status of the drug. Once it’s approved, the drug can then be launched in the market place and sold to the public.

In summary, drug discovery and development is a long and costly process. It has to go through multiple steps to transform a chemical compound into useful drug.

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