DRUG DESIGN: A CONCEPTUAL APPROACH
May 14, 2009 – 1:57 pm
Successful drug design is multi-step, multidisciplinary and multi-year. Drug discovery is not an inevitable consequence of fundamental basic science; drug design is not merely a technology that generates drugs for humans on the basis of biological advances—if itwere that simple, more and better drugs would already be available.
Medicinal chemistry is a science unto itself, a central science positioned to provide a molecular bridge between the basic science of biology and the clinical science of medicine (analogous to chemistry being the central science between the traditional disciplines of biology and physics). From a very broad perspective, drug design may be divided into two phases:
1. Basic concepts about drugs, receptors, and drug–receptor interactions
2. Basic concepts about drug–receptor interactions applied to human disease
The first phase comprises the essential building blocks of drug design and may be divided into three logical steps:
1. Know what properties turn a molecule into a drug
2. Know what properties turn a macromolecule into a drug receptor
3. Know how to design and synthesize a drug to fit into a receptor
Knowledge of these three steps provides the necessary background required for a researcher to sit down, paper in hand, and start the process of creating a molecule as a potential drug for treating human disease.
Step 1 involves knowing what properties turn a molecule into a drug. All drugs may be molecules, but all molecules are certainly not drugs. Drug molecules are “small” organic molecules (molecular weight usually below 800 g/mol, often below 500). Penicillin, acetylsalicyclic acid, and morphine are all small organic molecules. Certain properties (geometric, conformational, stereochemical, electronic) must be controlled if a molecule is going to have what it takes even to emerge as a drug-like molecule (DLM).
When designing a molecule to be a drug-like molecule and, hopefully, a drug, the designer must have the ability to use diverse design tools. Now, computer-aided molecular design (CAMD) is one of the most important design tools available. CAMD incorporates various rigorous mathematical techniques, including molecular mechanics and quantum mechanics. When using CAMD to design a drug, one must remember that a drug molecule is complex and has sub-unit parts. Some of these parts enable the drug to interact with its receptor, while other parts permit the body to absorb, distribute, metabolize, and excrete the drug molecule. Once a drug-like molecule successfully becomes a candidate for the treatment of a disease, it has graduated to the status of drug molecule.
Step 2 involves knowing what properties turn a macromolecule into a receptor. All receptors may be macromolecules, but all macromolecules are certainly not receptors. Receptor macromolecules are frequently proteins or glycoproteins. Certain properties must be present if a macromolecule is going to have what it takes to be a druggable target. The receptor macromolecule must be intimately connected with the disease in question, but not integral to the normal biochemistry of a wide range of processes.
Step 3 involves designing a specific drug-like molecule to fit into a particular druggable target. During this task many molecules will be considered, but only one (or two) will emerge as promising starting points around which to further elaborate the design process. This prototype compound is referred to as the lead compound. There is a varietyof ways of identifying a potential lead compound, including rational drug design, random high throughput screening, and focused library screening. Once a lead compound has been successfully identified, it must be optimized. Optimization may be achieved using quantitative structure–activity relationship (QSAR) studies. Synthetic organic chemistry is a crucial component of this step in drug development. The process of drug design must be validated by actually making and testing the drug molecule. An ideal synthesis should be simple, be efficient, and produce the drug in high yield and high
purity.
Once the basics of drug design are in place, the drug designer next focuses upon the task of connecting a drug–receptor interaction to a human disease—this is the goal of the second phase. For example, how does one design a drug for the treatment of cancer or Alzheimer’s disease? This phase of drug design requires an understanding of biochemistry and of the molecular pathology of the disease being treated.
The human body normally moves through time with its various molecular processes functioning in a balanced, harmonious state, called homeostasis. When disease occurs, this balance is perturbed by a pathological process. For a drug molecule, the goal is to rectify this perturbation (via the action of molecular therapeutics) and to return the body to a state of healthy homeostasis.
Logically, there are many approaches to attaining this therapeutic goal. First, one may ask what are the body’s normal inner (endogenous) control systems for maintaining homeostasis through day-to-day or minute-to-minute adjustments? These control systems (for example, neurotransmitters, hormones, immunomodulators) are the first line of defense against perturbations of homeostasis.
Is it possible for the drug designer to exploit these existing control systems to deal with some pathological process? If there are no endogenous control systems, how about identifying other targets on endogenous cellular structures or macromolecules that will permit control where endogenous control has not previously existed? Alternatively, instead of pursuing these endogenous approaches, it is sometimes easier simply to attack the cause of the pathology.
If there is a harmful microorganism or toxin in the environment (exogenous), then it may be possible to directly attack this exogenous threat to health and inactivate it. Accordingly, this phase of drug development, which connects the drug–receptor interaction to human disease, may be divided into three logical approaches:
1. Know how to manipulate the body’s endogenous control systems
2. Know how to manipulate the body’s endogenous macromolecules
3. Know how to inactivate a harmful exogenous substance
A full understanding of the three steps of phase 1 and the three approaches of phase 2 will enable the researcher to design drugs.
