Pharmaceutical Chemistry

Pharmaceutical chemists are involved in the development and assessment of therapeutic compounds. Pharmaceutical chemistry encompasses drug design, drug synthesis , and the evaluation of drug efficacy (how effective it is in treating a condition) and drug safety. Prior to the nineteenth century, schools of pharmacy trained pharmacists and physicians how to prepare medicinal remedies from natural organic products or inorganic materials. Herbal medications and folk remedies dating back to ancient Egyptian, Greek, Roman, and Asian societies were administered without any knowledge of their biological mechanism of action. It was not until the early 1800s that scientists began extracting chemicals from plants with purported therapeutic properties to isolate the active components and identify them. By discovering and structurally characterizing compounds with medicinal activity, chemists are able to design new drugs with enhanced potency and decreased adverse side effects.

Drug discovery is the core of pharmaceutical chemistry. The drug discovery process includes all the stages of drug development, from targeting a disease or medical condition to toxicity studies in animals, or even, by some definitions, testing the drug on human subjects. Typically, conditions that affect a larger percentage of the population receive more attention and more research funding. Antiulcer drugs and cholesterol- reducing agents are currently the therapeutic areas of greatest emphasis. To develop a drug to target a specific disease, researchers try to understand the biological mechanism responsible for that condition. If the biochemical pathways leading up to the disease are understood, scientists attempt to design drugs that will block one or several of the steps of the disease's progress. Alternatively, drugs that boost the body's own defense mechanism may be appropriate.

How do chemists "discover" drugs? Often there is an existing remedy for a condition, and scientists will evaluate how that drug exerts its actions. Once the drug's structure is known, the drug can serve as a prototype or "lead compound" for designing more effective therapeutic agents of similar chemical structure. Lead compounds are molecules that have some biological activity with respect to the condition under investigation. However, the lead compound may not be effective in combating the disease, or it may produce undesirable side effects. Lead optimization involves chemical modifications to the lead compound to produce a more potent drug, or one with fewer or decreased adverse effects.

Computers have transformed the drug discovery process. Rational drug design involves computer-assisted approaches to designing molecules with desired chemical properties. Rational drug design is based on a molecular understanding of the interactions between the drug and its target in biological systems. Molecular modeling software depicts three-dimensional images of a chemical. Mathematical operations adjust the positions of the atoms in the molecule in an attempt to accurately portray the size and shape of the drug, and the location of any charged groups. Chemists can vary the atoms or groups within the model and predict the effect the transformation has on the molecular properties of the drug. In this way, new compounds can be designed.

Advances in technology have made it possible for medicinal chemists to synthesize a vast number of compounds in a relatively short time, a process referred to as combinatorial chemistry. In this technique, one part of a molecule is maintained, as different chemical groups are attached to its molecular framework to produce a series of similar molecules with distinct structural variations. Combinatorial libraries of these molecular variants are thus created.

Every chemical that is synthesized must be tested for biological activity. In vitro testing involves biological assays outside a living system. For example, if the desired effect of a drug is to inhibit a particular enzyme, the enzyme can be isolated from an organ and studied in a test tube. New technologies have made it possible to assay large numbers of compounds in a short period. High-throughput drug screening allows pharmaceutical chemists to test between 1,000 and 100,000 chemicals in a single day! A compound that demonstrates some biological activity will undergo further tests, or it may be chemically modified to enhance its activity. As a consequence, chemical libraries consisting of potentially therapeutic compounds are developed. Each of these compounds can then serve as leads for the development of new drugs to be screened.

Once a drug shows promise in vitro as a therapeutic agent, it must also be screened for toxic properties. Adverse drug side effects are often due to the interaction of the drug with biological molecules other than the desired target. It is very rare that a drug interacts with only one type of molecule in a living system. Drug selectivity refers to the ability of the compound to interact with its target, not with other proteins or enzymes in the system. To investigate drug toxicity, animal studies are performed. These studies also estimate mutagenicity, that is, whether the compound under investigation damages genetic material.

Rarely does a drug pass through a biological system unchanged. Most drugs undergo chemical transformations (in a process known as drug metabolism ) before they are excreted from the body. The drug transformation products ( metabolites ) must be identified so that their toxicological profiles can be determined.

Since the 1970s more attention has been given to drug formulation and methods of drug delivery. Historically, drugs have been administered orally, as a pill or a liquid, or in an injectable form. The goal of drug-delivery systems is to enable controlled and targeted drug release. Today, many medications are commonly introduced as inhalants or in a time-release formulation, either encapsulated in a biodegradable polymer or by means of a transdermal patch.

Once scientists and government regulatory agencies have determined the drug candidate to be relatively safe, it can enter into clinical trials. The clinical stage involves four phases of testing on human volunteers. Animal studies and in vitro testing continue during clinical investigations of a drug. Drug-therapy evaluation is very costly and time consuming. Phase I clinical trials evaluate drug tolerance and safety in a small group of healthy adult volunteers. Phase II trials continue to assess the drug's safety and effectiveness in a larger population. Volunteers participating in phase I trials understand that they are receiving experimental therapy. While those patients involved in phase II clinical trials are made aware of the medication and any known side effects, some of the volunteers may be administered a placebo (a compound with no pharmacological activity against the condition being treated) rather than the drug being studied. In a blind study, only the physician administering therapy knows whether the patient is receiving the drug or a placebo. Both groups of patients are monitored, and physicians or clinicians evaluate whether there is significant improvement in the condition of the group receiving the experimental drug, compared with those individuals who were administered a placebo. In a double-blind study, neither the physician nor the patient knows whether the drug, a placebo, or a related remedy has been administered. Therapy is monitored by an outside group.

Phase III and phase IV clinical trials involve larger populations. During phase III trials, which can last two to eight years, a drug is often brought to market. Phase IV studies continue after the drug is being marketed.

The field of pharmaceutical chemistry is diverse and involves many areas of expertise. Natural-product and analytical chemists isolate and identify active components from plant and other natural sources. Theoretical chemists construct molecular models of existing drugs to evaluate their properties. These computational studies help medicinal chemists and bioengineers design and synthesize compounds with enhanced biological activity. Pharmaceutical chemists evaluate the bioactivity of drugs and drug metabolites. Toxicologists assess drug safety and potential adverse effects of drug therapy. When a drug has been approved for human studies, clinicians and physicians monitor patients' response to treatment with the new drug. The impact of pharmaceutical chemistry on the normal human life span and on the quality of life enjoyed by most people is hard to overestimate.

SEE ALSO Combinatorial Chemistry ; Computational Chemistry ; Molecular Modeling .

Nanette M. Wachter


Vogelson, Cullen T. (2001). "Advances in Drug Delivery Systems." Modern Drug Discovery 4(4):49–50, 52.

Williams, David A., and Lemke, Thomas L. (2002). Foye's Principles of Medicinal Chemistry, 5th edition. Philadelphia: Lippincott Williams & Wilkins.

Wolff, Manfred E., ed. (1996). Burger's Medicinal Chemistry and Drug Discovery, 5th edition. New York: Wiley.

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