Principles of Early Drug Discovery

It sounds absolutely unappealing to live without those fast-relief drugs like aspirin to get rid of your daily dose of migraines! That’s why these drugs are manufactured for serving human needs. However, drug development first has to go through some early drug discovery principles.

Drug discovery is a very lengthy procedure. It is usually carried out wherever a recent outbreak affects the whole nation with no possible drugs discovered for its treatment. 

The early drug discovery period consists of numerous steps and trials. Firstly a plethora of compounds are tested in order to identify the leading compound according to its target. This is used to activate proteins for achieving therapeutic responses. Finally, the overall drug is developed based on this.

Stay tuned as we collected instructions for the early drug discovery principles.

Principles of Early Drug Discovery

Early drug discovery identifies the accurate chemical compounds for treating a particular disease. This is basically the starting point of the overall drug development system. Its principles include:

Target Identification and Validation

A molecular target, specifically proteins, genes, and nuclear acids need to be identified before moving on to the drug discovery procedures. Biological targets are considered “druggable” only if a specific therapeutical model called “hit” alters its functionality. 

The targets should have a toxicity profile for early identification of any underlying side effects.

The pathogenesis of an illness also needs to be understood in order to identify the most suitable targets. These targets are usually recognized by data mining through previously collected data. 

There are two other procedures for target identification. Target deconvolution involving known targets with active hits is used to understand the mechanism of a drug. Another one is target discovery which is self-explanatory. Here, the target is screened to find the most appropriate result.

Now after the identification of the target, its validation process begins. Here, research is carried out to analyze if the target is suitable to develop drugs.

The experiment is first repeated to confirm the target’s functionality as well as reproducibility. Next, the activity of the drug sample is modified by varying the cell type. This along with mutations in the binding site confirms drug validation if any changes are observed.

Thus, a target for drug discovery is confirmed. 

High Throughput Screening (HTS) and High Content Screening (HCS)

Once the target is identified and validated, screening procedures take over. Screening includes high-throughput screening (HTS) and high-content screening (HCS). These are the analytical techniques for studying biological molecules. 

HTS mainly consists of optical detection for more accurate identification of target molecules. It utilizes sensitive detectors and robotics for carrying out pharmacological tests faster. This aids in the analysis of antibiotics that work better with particular molecular pathways. 

This screening technique also maneuvers microplates that can automatically identify a wide variety of samples. Targets like receptors are screened based on their biological activity.

HCS is the other procedure that mostly focuses on cell analysis. Here, cells are the detection objects in the case of microscopic imaging. It aids in observing the activities going on inside cells. 

Live cell imaging is carried out where information about the cells is collected very efficiently. Elements of HCS include automated fluorescence image acquisition, detection tools, and result analysis.

Overall, HCS is considered slightly better than HTS for detecting effects on a number of cell characteristics. Very detailed new information about genes can be curated including their toxicology reports using this experiment.

This is how drug discovery is facilitated using both of these automated techniques.

Hit Generation and Optimization

This step consists of a wide generation of drug candidates called “hits” that are in the binding domain with the target. There are multiple approaches for identifying hit molecules.

Along with HTS and HCS, more advanced screening procedures are implemented. 

Fragment-based drug discovery (FBDD) is one of the most powerful methods for screening. It integrates fragments of small-sized compounds binding less tightly to targets. Fragment-based screening techniques consist of nuclear magnetic resonance, surface plasmon resonance, and X-ray crystallography.

The fragment library for screening contains minute molecules for drug efficiency. Again Differential scanning fluorimetry measures the denaturing of protein when subjected to fluorescence dye. 

Structure-based virtual screening is an essential computational tool for faster and more cost-efficient hit discovery. A three-dimensional structure of the target is achieved from X-rays in order to obtain these compounds for further evaluation. All these compounds are ranked based on how strongly they are bound to the targets.

Psychological screening is another method where stem cell derived from cardiac tissue acts as a model. The condition of the heart relevant to the disease along with adverse drug effects improves the efficacy of the drug.

In this way hit generation and discovery enable finding the most powerful hits.

Assay Development and Screening

The creation of test systems called assays is crucial for drug discovery. It is applied to evaluate the impacts of chemical compounds on cellular or biochemical processes

Assays qualitatively assess a compound by identifying its biochemical targets. The quality of an assay is identified by the robustness of the signal. The signal measured could depend on fluorescence, radioactivity, and reaction conditions for the data analysis.

It assists in screening compounds to analyze their interaction with the target. Interaction can also lead o the modification of the target. By determining specific pathways, researchers to can now enhance comprehensive assays using modern emerging tools.

Assays can be both cell-free and cell-based procedures. These can be detected using colorimetric, fluorescence, and bioluminescence.

So assays can examine biochemical compounds.

Hit-to-Lead (H2L)

According to its name, the hit-to-lead technique aims to discover compounds from a selection of chemical compounds presenting therapeutic effects. A hit is a term used for the therapeutic chemical compound that possesses an effect on target molecules. Similarly, the lead is the result of the screening methods. 

The goal of this process is to identify the most applicable leads to finally achieve a clinically active drug. Further screening helps to narrow down the lead molecules for more accurate results. Activity levels can be determined by measuring its acuteness and porousness. 

However, researchers often come across a challenge. It is difficult to optimize only one property without compromising another property. To overcome these, parallel optimization is usually conducted.

This means that hit-to-lead determines its most appropriate targeted lead.

Lead Generation and Optimization

Lead optimization assists in the identification of a preclinical candidate. The hit candidates now advance toward lead optimization. 

Its goal is to solely contribute towards optimization.  Successful lead optimization methods in drug discovery include safety and require collaboration. Screening assays are also developed for evaluating physiochemical properties. This helps to identify the most suitable compound ready to be formulated. 

Rigorous data is bound to be collected for a better evaluation process. Remember the better the quality of preclinical candidates, the more guarantee of a successful progression in drug discovery.

Lead optimization includes multi-parametric optimization of the best set of biochemical compounds. It also maximizes potency and minimizes toxicity. Not only these but human dose predictions can also be accurately done.

Therefore lead generation ensures the optimization of a certain batch of lead molecules.

In Vivo and In Vitro​ Assays

Finally, the resultant potential candidates are examined in conditions similar to living conditions. In vitro testing comes first and in vivo comes later.

In-vitro is usually carried out outside living cells. It means that the cells or pathogens are collected in Petri dishes and are analyzed thoroughly in laboratories. Here, the petri dish acts as a controlled environment. This technique is usually better as there are no other bodily distractions. 

Target cells are exposed to a novel drug in order to observe the effects. This is used for identifying any toxic reactions. However, living conditions cannot be replicated using this. So in-vivo testing needs to be carried out.

In-vivo revolves around the concept of conducting research in the living body. Performing in-vivo assays exposes the drug to actual living beings. It means that any kind of allergies and other adverse effects can be identified. Zebrafish are typically used in in vivo and in vitro assays.

Bottom Line 

The early stages of drug discovery involve multiple stages for detecting molecules appropriate for drug development. It is very time-consuming – may sometimes take over a decade to develop. By now you are surely more familiar with the entire principles of early drug delivery. 

To sum it up, new drugs are required whenever rare conditions become more viable. So the early stages of drug delivery assist in identifying the core of the disease. Firstly, a possible candidate for the molecular target is identified. 

Next, these extracted compounds are analyzed with the help of High Throughput and High Content Throughput Screenings. Therapeutic candidates called hits are obtained and examined based on how strongly it’s attached to the target. 

For the evaluation of compounds, assays are also developed. After that, hit-to-lead ensures the achievement of a clinically active drug. Lead generation contributes to its optimization. And finally, in vitro and vivo assays are used for further research.