# Structural Biochemistry/Drug Development Challenges

Drug development today is constantly pressured from multiple different aspects due to the all-time low of drug approval on the market. Drug developers must acknowledge this trend even before the process begins. Unfortunately for some companies, resources are already limited and do not have the luxury of researching and developing as easily as others.

## Challenges

Regulatory requirements and commitments are continually increasing over time and have effected the trial size and length. This has led to an overall increase in total cost of drug development. The FDA now requires more sample trials in order to be approved, this is to ensure safety and efficacy.
Due to the increase in clinical trials, it has become necessary for trials to occur in foreign countries. Unfortunately, each country has its own set of regulations for drugs, further increasing the difficulty of trials.
Electronic submission to regulatory authorities has become mandatory in some countries such as the US. The transition to the Electronic Common Technical Document (eCTD), will soon become the mandatory and preferred way of submission. While the eCTD does come with many benefits, developing countries must quickly adapt to the system, further slowing the development process of drugs.
Drug administrations and absorption levels linked to the effect and side effect of the drug are a crucial part of the process.

## Challenges of Drug Development

Many compounds have significant effects when taken into the body, but only every small fraction of them have the potential to become useful drugs. A foreign compound, synthesized in a wet lab or extracted from nature, must be able to adapt in the cells of an organism to function effectively without causing any serious harm. Drug candidates must be potent modulators of their targets as wee have suitable properties to reach their targets

### Drug Candidates must be Potent

For drugs to be effective, it needs to bind a sufficient number of its target proteins when taken at a reasonable dose. One factor in determing drug effectiveness is the strength of the interaction between the drug and its target. A molecule that binds to some target molecule is often referred to as a ligand. Ligand molecules occupy progressively more target binding sites as ligand concentrations increases until essentially all of the available sites are occupied. This tendency of a ligand to bind to its target is measured by the dissociation constant, K$_d$
where [R] is the concentration of the free receptor, [L] is the concentration of the free ligand, and [RL] is the concentration of the receptor-ligand complex. The dissociation constant value is a measure of the strength of the interaction between the drug candidate and the target; the lower the value, the stronger the interaction. The concentration of free ligand at which one-half of the binding sites are occupied equals the dissociation constant, as long as the concentration of binding sites is substantially less than the dissociation constant.
However, sometimes in the cases of biological assays where drug candidates are utilized on living cells or tissues, an alternative method is used to determine the potency of a drug. In these cases, the EC$_{50}$ concentration is measured. This is the concentration of the drug candidate required to elicit 50% of the maximal biological response. For drug candidates that are inhibitors (ex. sodium channel blockers), the term IC$_{50}$ is used to describe the concentration of the inhibitor required to reduce a response to 50% of its value in the absence of inhibitor.
(K$_i$ is known as the inhibition constant; K$_M$ is the Michaelis constant for the substrate S. The higher the concentration of the natural substrate, the higher the concentration of drug needed to inhibit the enzyme to a given extent.
IC$_{50}$ and EC$_{50}$ values are important measures of potency of a drug candidate in evaluating the activity of the desired biological target. Oftentimes a drug target is a member of a large family of proteins that similar in nature, which can be extremely challenging when developing a target drug.

### Drug Candidates must have suitable properties to reach targets

In addition to the ability of molecules to act on specific target molecules, an effective drug must also have other characteristics. For example, it must be easily administered and reach its target at sufficient concentration to be effective, a drug molecule encounters a variety of obstacles on its way to its target. The following properties are the four basic stages of a medicine's life in the body:
1. Absorption
2. Distribution
3. Metabolism
4. Excretion

### Absorption

Drugs can be taken orally as a small tablet and must be able to survive the acidic conditions in the gut and then be absorbed through the intestinal epithelium. A few of the most common ways to administer drugs are oral (swallowing an aspirin tablet), intramuscular (getting a flu shot in an arm muscle), subcutaneous (an injection of insulin under the skin), intravenous (receiving chemotherapy through a vein), or transdermal (wearing a skin patch). Drugs face a great deal of hurdles during absorption, because of the liver and the great deal of variability in drug administration in the human body. There are a set of rules that tells us when poor absorption is likely:
1. molecular weight is >500 g/mol
2. number of hydrogen bond donors is greater than 5
3. number of hydrogen bond acceptors is greater than 10
4. partition coefficient is greater than 5 (way to measure the tendency of a molecule to dissolve cell membranes)
The challenge with the liver is that the liver will filter most of the drugs away before it will reach the bloodstream. Metabolic enzymes would break down the drug rendering it useless. This would lead to most of the drugs not reaching the target organs, or not having any effect. In order to bypass this, the many different absorption methods are introduced.(2)

### Distribution

Once a drug is absorbed, the next stage is the distribution of the drug. Most often, the bloodstream is the primary means of transportation for drugs. Once the drug reaches the bloodstream, it is distributed to different fluids and tissues. This is the step that leads to a wide array of side effects in organs throughout the body. However it is important to note that some organs have stronger defense systems than others. For example, the central nervous system has a strong blood brain barrier that protects the brain from dangerous poisons or viruses.
Another challenge during the distribution of the drug throughout the body is its attachment to other molecules besides the receptors of the target organ. Drugs could react with compounds present in the blood of the patient and could end up rendering the drug useless, or could produce unwanted side effects. Also, because the compound is spread all over the body, non-target organs with specialized cells and unique receptors could end up reacting and attaching to the drug. If the drug attaches to a receptor and activates, or activates a function of the cell, it could lead to unwanted side effects that could be potentially harmful or fatal.(2)

### Metabolism

After a drug has been distributed throughout the body and has done its job, the medicine is broken down or metabolized. The metabolism generally occurs in the liver. The liver is the site of continuous yet controlled activity. Everything that enters the bloodstream is carried straight to the intestine. In the intestine, molecules and substances are chemically and physically metabolized.

### Excretion

Once a drug is absorbed and carries out its specific biological tasks, it must be converted into a substance that can be physically excreted. The liver detoxifies the drug's components using chemical metabolites, which then exits via the urine or feces.

## References

1. Berg J, Tymoczko J, Lubert S: Biochemistry, 7th Edition
2. Medicine by Design, US Department of Health and Human Services,NIH Publications, Reprinted July 2006

## References

1. Berg J, Tymoczko J, Lubert S: Biochemistry, 7th Edition 2. Singh, Harjit. Drug Development Challenges. Pharma. <http://www.pharmafocusasia.com/strategy/drug_development_challenges.htm> 3. Medicine by Design National Institute of Health