Drug Discovery and Development

Abstract

[...]prudent investments and measured risks at this eventually, a specific moment can raise the risk of success for a new Potential4,6. The different stages or phases of the drug development and discovery process are20-24 Drug Discovery Period25-31 * Initiate drug discovery program Combinatorial chemistry * Lead compound series identification * Additional compounds are made NCE’ s identified Drug Development and Registration Period32-35 * IND plan established and initiated * IND filed * Clinical studies initiated * NDA prepared and submitted * Drug launched into the market Drug Marketing and Line Expansion36-41 * Post-Marketing surveillance initiated * New clinical indications pursued * New dosage forms and formulations developed * Activities conducted to support marketing Drug Discovery and Development: Drug Discovery: New studies into a disease process that motivate scientists to create a new product to prevent or reverse the disease’s effects are the usual ways that researchers find new drugs42,44. * Numerous molecular compound tests to identify potential protective effects against a wide range of illnesses * Current therapies with unexpected side effects45–51 * New technologies, such as those that offer novel approaches to genetic material manipulation or the delivery of pharmaceuticals to particular bodily locations52–54. Drug Development: After discovering a compound that shows promise for development, scientists carry out tests in order to understand more about60–66: * Its distribution, metabolism, excretion, and absorption * Its possible advantages and modes of action * The ideal dosage and method of delivery * Adverse effects also known as toxicity * The ways in which it impacts different age groups (e.g., by gender, race, or ethnicity) differently * How it affects other medications and therapies * Its efficacy in comparison to comparable medications Preclinical Trials: ICH has established a basic guideline for the technical necessities of acceptable preclinical drug development. Prior to the start of a clinical trial, researchers review existing data about the drug to formulate research questions and objectives75. * Selection criteria for participants * Number of people take part of the study * Duration of study * Dose and route of administration of dosage form * Assessment of parameters * Data collection and analysis Phase 1:

INTRODUCTION:

Since ancient times, humanity has been engaged in a never-ending battle with illnesses. Even if numerous pharmacological substances have been discovered and modified to increase their dependability for use as a remedy, there are still numerous obstacles that prevent them from being effective enough to be deemed a “successful” discovery1. A new molecule is created or released onto the market for the good of society after a lengthy process known as drug discovery. In overall, the drug development process takes 12 to 15 years to produce a drug molecule completely developed into a novel medication candidate2.

We are able to guess on how long this process will take and how much money will need to be spent before it can be released onto the market. From the beginning of the drug discovery process to a possible cure, it costs more than $1 billion potential medication3. The process of drug discovery involves several phases of drug development, including initial hit identification, pre-clinical and clinical studies, FDA review, and post- marketing surveillance to monitor the Efficacy of the medication once a large population has been reached4.

In this Review, we will go over each step in detail to have a better understanding of thorough understanding of the domain and its present state. The intricate path a drug takes this entire procedure necessitated that the researchers go through advanced preclinical research, applications for investigational new drugs (INDs), and Clinical trials prior to a medication’s eventual approval for sale from the FDA5. Researchers may investigate into fresh perspectives on the development or progression of a disease, which may reveal a new pathway that a novel medication can target4. As an alternative, many businesses carry out a thorough trial procedure to determine the compound of interest. Actually, prudent investments and measured risks at this eventually, a specific moment can raise the risk of success for a new Potential4,6. These days, the drug discovery process goes all the way from Using computer simulation software to screen hits in silicon through hit detection, improvement and molecular testing to reduce adverse effects, until the creation of a novel medication candidate7. Drug discovery has advanced significantly in recent years, largely due to advancements in molecular biology, computer-aided drug design software, medicinal chemistry, and chemistry of organic matter1. Drug discoveries were previously the result of serendipity and a continuous trial-and-error experimental process that could eventually derive into an unknown substance, later coming to be known as a drug; the discovery of penicillin is one such example9,10. Molecular biological disciplines’ thorough understanding of disease pathophysiology also aided in the discovery and development process8. Drug discoveries only began to actively enter the pipeline in the 1980s.It takes much longer and requires much more complex clinical data to report safety and efficacy on human subjects11,12. After a complete medical evaluation, the ultimate goal of drug discovery is to quickly introduce a safer and more effective medication to the market13,14

Drug Discovery consist of 4 major steps, including few subdivision in each of them:

1. Pre discovery

2. Preclinical Trials

3. Clinical Trials

4. Post marketing surveillance15

Objectives16

* Recognize the investigational drug success rates by stages.

* Define Pre-clinical studies

* Define Investigational New Drug Application – Phase I, Phase II, Phase III studies

* Define New Drug Application

* Define Phase IV studies

Periods in Drug Discovery and Development Process:

The entire drug discovery and development process, including its introduction into the commercial market, is thought to take five to ten years and cost approximately $1.7 billion to complete successfully [17-19]. The different stages or phases of the drug development and discovery process are20-24

Drug Discovery Period25-31

* Initiate drug discovery program Combinatorial chemistry

* Lead compound series identification

* Additional compounds are made NCE’ s identified

Drug Development and Registration Period32-35

* IND plan established and initiated

* IND filed

* Clinical studies initiated

* NDA prepared and submitted

* Drug launched into the market

Drug Marketing and Line Expansion36-41

* Post-Marketing surveillance initiated

* New clinical indications pursued

* New dosage forms and formulations developed

* Activities conducted to support marketing

Drug Discovery and Development:

Drug Discovery:

New studies into a disease process that motivate scientists to create a new product to prevent or reverse the disease’s effects are the usual ways that researchers find new drugs42,44.

* Numerous molecular compound tests to identify potential protective effects against a wide range of illnesses

* Current therapies with unexpected side effects45–51

* New technologies, such as those that offer novel approaches to genetic material manipulation or the delivery of pharmaceuticals to particular bodily locations52–54. Thousands of compounds could be viable candidates for medical treatment development at this point. However, only a few compounds appear promising after preliminary testing and allow additional research55–59.

Drug Development:

After discovering a compound that shows promise for development, scientists carry out tests in order to understand more about60–66:

* Its distribution, metabolism, excretion, and absorption

* Its possible advantages and modes of action

* The ideal dosage and method of delivery

* Adverse effects also known as toxicity

* The ways in which it impacts different age groups (e.g., by gender, race, or ethnicity) differently

* How it affects other medications and therapies

* Its efficacy in comparison to comparable medications

Preclinical Trials:

ICH has established a basic guideline for the technical necessities of acceptable preclinical drug development. Preclinical research in the drug development process involves evaluating the drug’s safety and efficacy in animal species that conclude to prospective human outcome. Preclinical trials also need to obtain approval from the relevant regulatory authorities, who must ensure that trials are conducted in a safe and ethical manner and would only give approval for those drugs which are confirmed to be safe and effective67,68.

There are two methods for carrying out the pre-clinical trials: toxicology and general pharmacology. The pharmacokinetic and pharmacodynamic characteristics of drugs are the focus of pharmacology.

Investigating undesirable pharmacological effects in appropriate animal models and keeping an eye on them in toxicological research are crucial. Pharmacokinetic studies are essential for determining the parameters of safety and efficacy in terms of distribution, metabolism, excretion, and absorption. These studies provide data on the rate of absorption for various administration routes, which aids in the choice of dosage form, distribution, metabolism rate, and elimination rate—all of which influence the drug’s half-life. The drug’s half-life provides clarification on its safety profile, which is necessary for regulatory bodies to approve a medication. The drug’s therapeutic efficacy is explained by its distribution mechanism, which is dependent on both its affinity and bioavailability. The possibility of going through stages of the biotransformation process and the production of drug metabolites is provided by drug metabolism. It also aids in absorbing the enzymes and reactions that take place during biotransformation69.

Both in-vitro and in-vivo tests that assess the drug’s toxicological effects can be used to conduct toxicological studies. The direct effects on cell proliferation and phenotype can be examined through in-vitro investigations. Toxicological effects can be determined both qualitatively and quantitatively through in-vivo investigations. Choosing the right animal species for a toxicity study is crucial because many medications are species specific. Clinical studies frequently rely on in- vivo investigations to assess the product’s pharmacological and toxicological effects, including its mode of action70-72.

The Investigational New Drug Process (IND):

Before starting clinical research, drug developers must submit an Investigational New Drug application to the FDA73. In the IND application, developers must include:

* Preclinical and toxicity study data

* Drug manufacturing information

* Clinical research protocols for studies to be conducted

* Previous clinical research data (if any)

* Information about the investigator/ developer74

Clinical Trials:

Clinical trials are carried out in individuals (volunteers) and have the purpose to provide answers to specific questions regarding the safety and effectiveness of medications, vaccines, other therapies, or novel ways to use existing treatments. Clinical trials conform to a specific study protocol that is created by the researcher, investigator, or manufacturer. As the developers design the clinical study, they will think about what they want to accomplish for each of the various Clinical Research Phases and begin the Investigational New Drug Process (IND), a procedure they must go through prior to clinical research. Prior to the start of a clinical trial, researchers review existing data about the drug to formulate research questions and objectives75.

* Selection criteria for participants

* Number of people take part of the study

* Duration of study

* Dose and route of administration of dosage form

* Assessment of parameters

* Data collection and analysis

Phase 1: Safety and dosage:

Phase I trials are the initial drug tests that involve lesser healthy human participants. Phase 1 typically involves 20 to 80 healthy volunteers who have the illness or condition. Patients are typically only used when a drug’s mechanism of action suggests that healthy individuals will not tolerate it. However, researchers perform Phase 1 trials on patients with that type of diabetes if a new medication is suggested for use in those patients. Pharmacodynamics in the human body are the subject of carefully monitored phase 1 studies. To determine what dosage a drug can tolerate in the body and what are its acute side effects, researchers modify the dosage schedule based on data from animal studies. Researchers understand the research mechanism of action, the side effects that come with increasing the dosage, and information regarding effectiveness as a Phase 1 trial progresses. This is essential for Phase 2 study design. Nearly 70% of medications advance to the following stage76.

Phase 2: Efficacy and side effects:

Phase II trials are carried out on larger patient populations (few hundred) with the goal of maintaining the Phase I safety evaluations and assessing the drug’s effectiveness. To determine whether the medication will be therapeutic, these trials are insufficient. Phase 2 studies give researchers more information about safety. These data are used by researchers to create new Phase3 research protocols, improve research methods, and enhance their research questions. Approximately 33% of medications advance to the following stages76.

Phase 3: Efficacy and adverse drug reactions monitoring:

Phase 3 studies are planned by researchers to demonstrate whether or not a product benefits a particular group of people. These studies, which include 300–3,000 volunteers, are sometimes referred to as pivotal studies. The majority of the safety data is provided by phase 3 studies. It’s possible that the earlier study ignored less frequent side effects. However, because phase 3 studies involve a larger number of volunteers and last longer, the findings are more likely to identify rare or long- lasting side effects. About 25–30% of medications advance to the following stage of clinical trials76.

New Drug Application:

The complete story of a drug molecule is expressed in a New Drug Application (NDA). Its goal is to confirm that a medication is both safe and effective for the intended use in the subjects of the study. The NDA must contain all information about a drug, from preclinical data to Phase 3 trial data. Reports on all studies, data, and analyses must be included by developers77. In addition to the results of clinical trials, developers need to include:

* Proposed labeling

* Safety updates

* Drug abuse information

* Patent information

* Institutional review board compliance information

* Directions for use

FDA Review:

After receiving a completed NDA, the FDA review team may need six to ten months to decide whether to approve the document. The FDA review team will reject the NDA if it receives an incomplete NDA.

Working with the developer to update prescribing information is crucial if the FDA determines that a drug has been found to be safe and effective for its intended use. Labeling is the term for this. The label clearly outlines the guidelines for drug use and the basis for approval. However, before the medication can be authorized for sale, the remaining problems must be resolved. In other situations, the FDA requires more research. The developer can decide at this point whether or not to carry out additional development. There are procedures for filing an official appeal if a developer disagrees with an FDA decisions78.

Phase 4: Post-Market Drug Safety Monitoring:

After the FDA has approved a drug or device, phase 4 trials are carried out. These studies are also known as post-marketing surveillance, which includes ongoing technical support and pharmacovigilance following approval. Phase 4 trials employ a variety of observational techniques and assessment patterns to measure the safety, cost-effectiveness, and effectiveness of an intervention in real-world situations. Phase IV studies may be conducted by the sponsoring company for competitive or other reasons, or they may be required by regulatory bodies (e.g., labeling changes, risk management/minimization action plans). As a result, the real picture of a drug’s safety basically takes place over the course of the months and even years that make up its shelf life. The FDA can decide to add precautions to the dosage or practice information, as well as other events for more serious adverse drug reactions, after reviewing reports of complications with both prescription and over-the-counter medications79,80.

Software Used in Drug Discovery:

Since the release of modern technology and associated tools, the drug discovery process has undergone significant development. These resources have not only helped to save time and effort, but they have also enhanced research results81. By boosting productivity in both the analytical and medicinal domains, these tools have assisted the pharmaceutical industries in staying competitive and up to date with the market. The creation of ChemDraw, a drawing tool that enables chemists worldwide to depict a compound’s structure in a very simple and direct manner, is one such important development82,83. One of its many important features is the ability to quickly identify the IUPAC names of the unique structures, along with their physical and chemical characteristics, among other things. AutoDock, Schrodinger, Discovery Studio, DDD Plus, MapCheck, and others are additional examples of this type84–87. In addition to saving the researchers a great deal of time and effort, these applications have improved the reproducibility and accuracy of the findings. The skill of capturing an image in a remarkable and complicated way that satisfies publishing requirements is a crucial component of data analysis or interpretation. By improving the generated image’s quality and impact, the software can help us in achieving the same goal88,89. Some of the common software used in the drug discovery process is listed in Table 1. It is outside the responsibility of this article to create all of the drug-related software’s examples and lists.

Table 1: List of most commonly used software in drug discovery

Sr. No	Name of the software	Original Use	Other use
1	ChemOffice	To draw chemical structures	Physical, chemical properties of a compound
2	AutoDock	Structure based drug design	Virtual screening, molecular docking
3	Schrodinger	Molecular modelling, simulation, dynamics	Protein structure analysis
4	ArgusLab	Drug designing	Molecular docking
5	Design-Expert	Optimization and screening of experiments	Validation response evaluation   of  experiments
6	QSAR-co	To develop QSAR models	Screening and Prediction of developed models
7	GraphPad prism	Statistical analysis of data	Comparison of significance of data
8	PyMol	For compound visualization	Pharmacophore modeling
9	Gromacs	Molecular dynamics	Simulation of amino acids, proteins etc.
10	Unipept	Metaproteomics study	Peptide characterization and analysis
11	Accord	Chem informatics	Storage and analysis of chemical structures
12	Jaguar	Quantum chemistry and calculations	Interpretation of spectrophotometric results
13	Gold	Flexible docking	Covalent docking pose prediction
14	SwissADME	Pharmacokinetics	Physicochemical evaluation
15	Ethowatcher	Behavioral analysis of animals	Physiological changes in laboratory animals

CONCLUSION:

New drugs are an important part of modern medicine with the emergence of diseases. A few decades ago, a disease such as peptic ulcers was an indication for major surgery. The advent of new pharmacologic treatments and introduction of novel medications have reduced the serious complications of peptic ulcer disease.

Similarly, thanks to many new antiviral medications with which the outlook for HIV- infected patients has improved. It is important that physicians understand the process of drug discovery and development. Understanding the process can promote innovation, help physicians assess new products, underline the importance of reporting adverse drug events and provide physicians with the information to educate patients about participating in a clinical trial.

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Credit: Kashish R. Mulani, B.P. Chaudhari, V. K. Redasani, Kalyani Gardi