Drug Discovery

Scientists normally search for molecules of either chemical or biological agents that can alter a disease process. They strive to find ways to change one or several molecular or cellular processes that occur in the affected cells of a diseased tissue or organ.

Initiating Drug Research:

To identify unknown medical need and current treatment procedure is the first step in this direction. Also the expertise needed, financial resource and regulatory considerations are taken into account.

Note: [According to the National center for Health in the United States, the top five diseases in 2005 were heart disease, cancer, stroke, chronic lower respiratory afflictions and diabetes.]

Target Discovery:

Identification of a medical necessity, and consideration of available financial resources, spurs scientists to examine closely the biology behind the disease. Since the human body is a very complex system, options are considered for intervening and earmarking the target. Target is a molecule and plays a crucial role in a disease. Then are 8000 known therapeutic targets in existence. These can be secreted factors, cell surface receptors or can point to pathways within a cell. The principle aim is to develop a drug which interferes with the disease process and ensures tangible benefits as well as minimizing side effects.

The therapeutic approach is not the same for all targets as their response is varied and so it is necessary to differentiate between healthy and diseased cells. The molecule is the main factor in a disease and the causes are many. In disease which is inherited it can be noted that, there is a difference in the expression and sequence of genes resulting in abnormal cell function. In some cases the target can be in excess, deficient or absent. So it becomes necessary to decide whether the target is to be blocked or enhanced or replaced for normal healthy function. Sometimes diseases are caused by external pathogen like virus or bacterium. The pathogen produces molecules thereby damaging host organism cells. Here the pathogen will display molecules in the individual so infected, contrary to that of a healthy person. The aim of target discovery is the detection of these different molecules by technology such as microarray, protein electrophoresis, Mass Spectrometry (MS), DNA sequencing and computerized imaging.

Since cell to cell interaction are very complex, the time taken in target discovery can span many years. There can be an involvement of multiple mechanisms and the points requiring intervention. The characteristics of a healthy or diseased cells can be very minute, complex and in some cases identification methods are yet to be invented.

Note: [The genetic and molecular basis of a disease is called the studying of disease mechanism.]

Target Validation:

After a target is identified it has to be validated. This comprises of two components, firstly to ascertain that the target molecule is responsible for the disease, and secondly to confirm the need for therapeutic intervention. The formulation of a safe and effective drug for human testing is considered and this process completes the second phase of target validation. Time, cost and technology are the prime concerns in target validation. At the basic level of this validation it is necessary to create the disease in a sample of healthy tissues and then block the target to restore healthy condition. This experiment is conducted in cell culture or animal models. The aim is to select the specific representative model which will work. Some people who are born without specific functional molecules express certain disease types. Samples derived from such individuals is another way of validating a target.

Target molecules includes receptors, enzymes, ion channels, growth factors, cytokines and DNA binding proteins. The common factor is the involvement of these targets in Signal Transduction processes within cells. Signal transduction pathways control cell division, differentiation, protein synthesis and programmed cell death (apoptosis). Cell culture is the initial phase of study and if found positive, then an animal model is used. Suitable animal model has to be created as it is not always easy to find one in an existing animal model or may not be similar to a human disease state. Sometimes a drug is specific to humans, unable to recognize the animal models target as the animal display immune response that negates any therapeutic effect. A disease in question is the Alzheimer’s syndrome. Only recently has research been done in mouse models. A study also analyzes the various effects of preclinical symptoms within the cell culture and animal models. At times the target is expressed on those cells and tissues besides the others in the disease process. Questions generally asked relate to cells and tissues of a drug candidate having adverse effect on other cells and tissues, does it give an immune response, does it stimulate similar targets or generate toxicity?

This preclinical work helps to establish further human trials if the drug candidate shows promise. Even if the drug gets marketing approval, surveillance continues after administration to patients.

Note: [Nowadays, Scientists use computer simulation to portray drug target interactions and it acts as a guideline to drug discovery.]


High-throughput screening is a combination process of robotics and data processing that quickly identifies the compounds, antibodies or genes that modulate a particular biomolecular pathway. Potential drugs are tested for binding or biological activity against target molecules. Once a diseased candidate gets verified, research labs develop a testing method called ASSAY in order to determine or measure pharmacological activity of hundred thousands of molecules.

The assay helps to measure the estimated potential of a molecule to block or simulate a target. The measurement can either be simply to know the potential of a drug candidate to kill cancer cells, or the complex measurement of inhibiting an enzyme involved in a disease. A complex assay gives out pertinent information but at a high cost and a long time schedule.

Molecules having positive therapeutic potential are called lead molecules as they are composed of drug like properties like solubility, permeability, and stability. Researchers can optimize a drug candidate’s ability to fight disease by changing its molecular structure, by application of combinatorial chemistry for small molecules and protein engineering for the larger variety.

Drug Design:

The basis of this design is in understanding the genetic and molecular base of a disease, and the information so given in selection of a specific therapeutic target. Drugs are designed to interact with the target. Rational drug design help in developing drugs suitable for a specific target in a disease. It also acts as a factor in achieving improved therapeutic potency with less side effects.

Scientists depend on image technology such as X-ray crystallography and 3-D structural information for enhancement of drug design strategies. If the target is on the exterior surface of the cell membrane or is secreted, protein therapeutics like monoclonal antibodies or peptides can be used. If they are on the interior of the cell, then only drugs that can cross the cell membrane like small molecules are used. The ultimate shape of a drug whether as a pill, liquid injection or spray determine the design of a drug candidate.