DRUG DESIGN: A PRACTICAL APPROACH
May 14, 2009 – 2:01 pm
This book aims to put forth a strategy to facilitate the insightful design of new chemical entities as therapies for human disease—a strategy that will foster the ability to sit down in front of a blank computer screen and draw molecules that may help cure the various maladies that afflict humankind. This strategy uses a molecular-level understanding ofhuman biochemistry and pathology to drive the design of drug-like molecules engineered to fit precisely into targets of drug action (druggable targets).
A Drug as a Composite of Molecular Fragments For the practical implementation of this idealistic strategy, drug molecules are conceptualized as being assembled from biologically active building blocks (biophores) that are covalently “snapped together” to form an overall molecule. Thus, a drug molecule is a multiphore, composed of a fragment that enables it to bind to a receptor (pharmacophore), a fragment that influences its metabolism in the body (metabophore), and one or more fragments that may contribute to toxicity (toxicophores).
The drug designer should have the ability to optimize the pharmacophore while minimizing the number of toxicophores. To achieve this design strategy, these fragments or building blocks may be replaced or nterchanged to modify the drug structure. Certain building blocks (called bioisosteres), which are biologically equivalent but not necessarily chemically equivalent, may be used to promote the optimization of the drug’s biological properties.
DRUG DESIGN: THE HUMANITARIAN APPROACH
In traditional medicine there are two major therapeutic approaches to the treatment of human disease: surgical and medical. Surgical procedures are labour intensive and time demanding; they help a limited number of individuals, one at a time, mostly in rich or developed nations.
Medical therapy, on the other hand, is based on drug molecules and thus has the capacity to positively influence the lives of more people, often over a shorter time frame. Medical therapeutics offer hope in both developed and developing parts of the world—hopefully to rich and poor alike.
After public health measures (e.g., safe drinking water, hygienic disposal of waste water), the discovery of drugs has had one of the largest beneficial effects on human health. Penicillin has saved countless lives through the effective treatment of devastating infectious diseases. Before penicillin, a diagnosis of meningococcal meningitis was invariably a death sentence. Penicillin reduced bacterial meningitis to a treatable disorder.
Similarly, drugs for the treatment of high blood pressure have substantially reduced the impact of this “silent killer” that leads to myocardial infarction (heart attack) or cerebral infarction (stroke).
It can be awe-inspiring to witness the effects of a seemingly trivial amount of drug. The panic-stricken child who cannot breathe because of an asthma attack gets prompt relief from the inhalation of a mere 100 micrograms of salbutamol sulphate. Uncontrolled and potentially life-threatening seizures (status epilepticus) in a young adult are quickly brought under control with the intravenous administration of 2 mg of lorazepam.
The terrified older adult with crushing chest pain from a myocardial infarction gains rapid relief from 8 to 10 mg of morphine. Drugs are truly amazing molecules. A medicinal chemist can help thousands or even millions of people with a carefully designed new drug molecule. The practice of science is a very human activity; medicinal chemistry is a humanitarian science.
