Usually, in drug discovery, a difference is made between the classical small molecule (traditional pharma) and biological products (biotech). Most drugs are small molecules. Small molecules are derived from a traditional chemical process (chemical synthesis) whereas biologic medicinal products may include recombinant proteins, vaccines, blood products used therapeutically (such as IVIG), gene therapy, and cell therapy (for instance, stem cell therapies).
Generally, a small molecule is an organic compound that regulates a biological process, with a low molecular weight (< 900 daltons) and a size on the order of 1 nm.
Large molecules are very large molecules, such as proteins or polymers. Typically, they are composed of thousands of atoms.
What are the different steps in drug Discovery research?
The principal objectives of the drug discovery research are to find suitable disease-related molecular targets and to identify new drug candidates that change the molecular action of the targets.
Drug candidates are then improved upon with medicinal chemistry and tested in preclinical studies on animals before clinical evaluation in humans. the ultimate goal is to provide sufficient evidence of the potential for efficacy safety and market approval.
In their article Mohs & Greig define that the goal of preclinical drug discovery is to produce candidate molecules that have enough proof of biologic target activity to a disease and sufficient safety and drug-like properties so that it can start human testing.
STEP 1: Target identification
Starting at the most fundamental level, scientists initiate studies to identify potential targets. A target is a structure involved in the pathology.
It can be cell-surface molecules like receptors, antigens on tumor cells, an ion channel or an enzyme. Read more on this here.
More recently, investments in finding new small-molecules have primarily been in the screening of large numbers (1000 – 1.000.000) of compounds.
Read more on this here.
Step 2: Target validation
Target validation makes sure that use of the target has likely therapeutic gain. It is the process where we verify the predicted molecular target like for example protein or nucleic acid. More on this here.
Once a company has a collection of targets, discovery researchers conduct experiments to provide evidence that the targets are associated with a particular disease state and that modulation of target activity could potentially provide therapeutic benefit.
Target validation may involve using knockout mice, or RNAi technology, or gene expression profiles, creating a drug-resistant mutant, knockdown or overexpression of the presumed target, and observing the known signaling processes downstream of the assumed target.
Note that a target is not truly “validated” until the drug candidate is shown to actually cure the disease in the affected population.
Step 3: Assay development
The definition of an assay on Wikipedia: “An assay is an investigative (analytic) procedure in laboratory medicine, pharmacology, environmental biology and molecular biology for qualitatively assessing or quantitatively measuring the presence, amount, or functional activity of a target entity (the analyte).”
Cell-based, binding or biochemical assays are designed to test whether the new chemical entities (NCEs) synthesized as part of a research project have the wanted effect on the specified target. Cell-based assays are also created to conclude how much of an NCE is required to change the activity of the target in order to produce the desired result. An extra objective is to grow assays that are so robust and consistent that they can operate in high-throughput screening mode.
Step 4: Lead or new chemical entity Discovery
After targets have been identified, scientists use the assays described above to find and evaluate NCEs. High throughput screening (HTS), in which millions of compounds can be tested against the targets to identify “hits” is a much-used technique. HTS is a somewhat random process, basically involving a brute force approach using libraries containing millions of NCEs. It is, however, unbiased and has revolutionized drug Discovery.
Most commonly used HTS analysis methods are fluorescence, chemiluminescence, and surface plasmon resonance (SPR). Imaduwage, Lakbub, Go and Desaire examine a new technique “Rapid LC-MS based HTS that does not suffer from the limitation that the above methods suffer from, namely “modification of the analytes or the protein is typically necessary for detection.” You can find that article here
Step 5: Lead optimization
The definition on Nature is:”Lead optimization is the process by which a drug candidate is designed after an initial lead compound is identified. The process involves iterative rounds of synthesis and characterization of a potential drug to build up a picture of how chemical structure and activity are related in terms of interactions with its targets and its metabolism.”
During lead optimization, functional characterizations are run to ensure that each NCE has the right pharmacokinetic and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles, plus the right biochemical properties for further development.
Medicinal chemists work to better pharmacokinetic profiles by producing products more potent, less toxic, less reactive, and more selective. As soon as NCEs are considered useful, they are analyzed to decide whether they have the wanted impact on the pathology in animal models in vitro and in vivo.
Step 6: Preclinical research
After an NCE has been shown to be biologically active and to have promising drug pharmacokinetic characteristics it goes to pre-clinical research.
The main objective is to understand what dose is safe before starting the first-in-man trial. Potential products are analyzed in complex animal disease models, and more detailed pharmacokinetic, toxicology, and dosage optimization studies are run. If this information is promising, it will eventually be included in the investigational new drug application (IND) required for entrance into phase 1 clinical trials.
Only 1 out 5.000 compounds that enter the pre-clinical stage eventually becomes an approved drug.
Step 7: Over and over again
All previous steps are part of an iterative process. Potent NCEs may go back and forth frequently between the medicinal chemistry group and the preclinical research group until a set of compounds with better pharmacokinetic profiles surfaces and the process is ready to go into clinical research.
Last modified: May 22, 2018