Everyone seemed to know how a new drug is created a long time ago, especially after covid-19, when everyone was watching those very clinical trials of vaccines. However, it's not that simple. In a nutshell — in this publication, you will learn how long the process of creating a drug takes and how expensive it is. And maybe you can guess that if they say on TV that scientists have discovered a substance that can beat cancer or some other disease, it's too early to run to the pharmacy hoping to buy this new medicine.
Historical background
Drug discovery started in ancient times, when natural products, mainly extracted from plants, were used for medicinal purposes in traditional medicine. In the following centuries, these compounds from plant sources led to the development of substances. This development and refinement strategy had a great impact in medicinal chemistry. One such example is the highly potent analgesic morphine, isolated from opium extracts by Sertüner in 1815. The emergence of analytical chemistry in the late nineteenth century made possible the isolation of individual bioactive ingredients from plant materials (although the purity levels were not of pharmaceutical grade by modern standards).
In 1908, Ehrlich’s investigations paved the way for the first rational synthetic drugs such as arsphenamine. Additionally, Ehrlich’s research team laid the foundations for reliable biological screening and evaluation procedures. At this stage, in the pre-NMR, pre-computational chemistry era, the chemists’ tools were somewhat limited. Hence, Institutional support and instrument development were fundamental in making the transition from chemical creativity to drug discovery. As such, one can say that «chance» was the basis for the discovery of penicillin by Alexander Fleming in 1928. Penicillin consists of a mixture of related betlactams sharing the same core structure. The strong antibiotic characteristic of penicillin was realized immediately.
Mass production of the antibiotic started around 1942 and had a significant impact on controlling sepsis during World War II. Penicillin was carried by Allied Medial Personnel during the D-Day landings. It is still used today in combating Gram positive micro-organism infections. The elucidation of the structure of the penicillin molecule led to a new successful era of antibiotics discovery, greatly improving healthcare in the treatment of bacterial infections. Contemporaneously, Chain, Florey, and their collaborators selected a metabolite from penicillium mould that could lyse Staphylococci. However, some of the antibiotics based on penicillin were degraded by protective enzymes produced by bacterial cells.
The discovery of new antibiotics through modification of the penicillin basic structure was intensified, in order to prevent bacterial degradation. In 1948, Brotzu reported a new molecule, referred as cephalosporin, that was used to treat infections resistant to penicillium. By then, many companies such as Merck, Sandoz, and Taked increased their microbiological facilities in order to find other drugs with different pharmacological and chemotherapeutic properties.
From 1950, the role of Medicinal Chemistry changed and can be divided into two important periods: from 1950 to 1980, Medicinal Chemistry was distinguished by in vivo tests; and the second era dating from 1980 to the present is distinguished by the emergence of new design and screening technologies. In the late 1960s and early 1970s, Beecham and Pfizer found new molecules with similar pharmacokinetic properties to penicillin – Beecham discovered clavulanates and Pfizer produced semisynthetic molecules known as sulfactams, in which the thiazoles sulphur was oxidized to the sulfone.
From the late 1980s onwards, the development of new technologies together with the advent of computational chemistry, meant that some of the aforementioned problems could be circumvented with relative ease. Indeed, since the early 1990s, rapid advances in molecular modelling tools, as well as the application of combinatorial chemistry and automated high-throughput screening, has brought immediate benefits in going from «lead discovery» to «lead optimization». Rationally designed libraries of compounds, based on known drug scaffolds can be generated in a relatively short space of time.
Rapid automated screening results in much shorter delay between delivering compounds and ascertaining the results of the screening. Screening data is then fed back into the SAR design process, leading to an iterative cycle of refinement, synthesis, and screening until the desired properties are achieved. By the close of the twentieth century, advances in molecular and cell biology such as recombinant DNA techniques helped to revolutionize the pharmaceutical industry. With the completion of the human genome project it became possible to gain a better understanding of the various molecular pathways responsible for certain diseases, and to use this information as a starting point in the search of new drugs based on proteins. Another technological breakthrough was the advent of hybridoma technology in 1975, which boosted the use of monoclonal antibodies as therapeutics.
As such, a transition period occurred between the twentieth and twenty-first centuries when the paradigms of molecular biology were associated with drug discovery. Genetic engineering led to the replacement of natural proteins by recombinant versions. This afforded several advantages in therapeutics. One such advantage was the greater safety of using recombinant-derived biopharmaceuticals, as opposed to proteins derived from human or animal sources which had the potential to cause transmission of infective agents. Additionally, it was possible to produce quantities of recombinant proteins in large scale; to develop new drugs directed to a target and the creation of engineered proteins with improved therapeutic properties.
Systems utilized to produce the majority of approved recombinant proteins were E. coli, S. cerevisiae, and animal cell lines such as Chinese hamster ovary (CHO) or baby hamster kidney (BHK). The first product resulting from DNA recombinant technology with approval for medical application in humans was human insulin produced in 1982, also known as «Humulin». A wide range of proteins for therapeutic purposes has been produced since then and by mid-2002, 120 biopharmaceuticals had obtained approval in the USA and/ or the EU.
These included a range of hormones (e.g. growth hormone), blood factors (e.g. factors VIII and IX), and thrombolytic agents (e.g. tissue plasminogen activator, tPA). By 2000, nearly 25% of all new drugs in development were monoclonal antibodies; in 2006, one of the top 200 prescribed drugs was a recombinant protein used to treat diabetes, as well as rheumatoid arthritis, Gaucher’s disease, and multiple sclerosis. New types of oral anti-HIV drugs – CCR5 antagonist Selzentry (maraviroc; Pfizer) and the HIV-1 integrase inhibitor Isentress (raltegravir; Merck) – were approved in 2007 by FDA for the treatment of HIV-1. Also new molecular entities as Torisel (temsirolimus; Wyeth) were approved in 2007 for the treatment of advanced renal cell carcinoma.
So, where does it start? — Idea
- In order for scientists or a pharmaceutical firm to begin developing a drug, there must be a combination of several factors:
- The social significance of the disease;
- Known molecular mechanisms of disease development;
- Financial resources and the ability to create a specific drug.
In other words, there must be an idea.
What constitutes a «target» for the drug?
Together, a team of scientists chooses a target and a way to target it in order to treat or prevent the disease.
A drug target is a biological macromolecule associated with a specific function, the disruption of which leads to a disease. The most common targets for drugs are proteins — receptors and enzymes. The infographic shows which macromolecules are most often targeted by drugs. Looking ahead, it is worth noting that the substance — the drug — is then matched to the «target». The most common example is cyclooxygenase 1 (target) and acetylsalicylic acid (drug).
Searching for ligands
Once scientists have found a target for a drug, they need to figure out what to «aim» at it with. A ligand (potential drug) is a chemical compound (usually low molecular weight) that specifically interacts with its target and thereby affects processes inside the cell.
The study of all possible substances is, of course, unrealistic: there are at least 1,040 ligands. Therefore, a number of restrictions are imposed on the structure of potential ligands, which significantly narrows the search.
What constitutes a «target» for the drug?
Together, a team of scientists chooses a target and a way to target it in order to treat or prevent the disease.
A drug target is a biological macromolecule associated with a specific function, the disruption of which leads to a disease. The most common targets for drugs are proteins — receptors and enzymes. The infographic shows which macromolecules are most often targeted by drugs. Looking ahead, it is worth noting that the substance — the drug — is then matched to the «target». The most common example is cyclooxygenase 1 (target) and acetylsalicylic acid (drug).
Searching for ligands
Once scientists have found a target for a drug, they need to figure out what to «aim» at it with. A ligand (potential drug) is a chemical compound (usually low molecular weight) that specifically interacts with its target and thereby affects processes inside the cell.
The study of all possible substances is, of course, unrealistic: there are at least 1,040 ligands. Therefore, a number of restrictions are imposed on the structure of potential ligands, which significantly narrows the search.
Initially, the screening assay helps to determine whether the selected ligands affect the target under study. The screening assay is either laboratory (in vitro) or computer (in silico).
Laboratory screening: on special slides, a robot digs test substances out of pipettes following a predetermined program.
The slides are plates containing wells with thousands of microliters of different target proteins or whole genetically modified cells.
Optimizing
Out of thousands of available substances with certain properties, hundreds of molecules should be selected that are capable, after further modification and testing on bacteria or cell cultures, of yielding dozens of «candidate» compounds intended for preclinical studies, including animal testing.
Optimization can consist in «cutting off» a part of the known ligand, or vice versa, adding new elements to it and new testing for interaction with the target. Going back to aspirin: it is derived from salicylic acid by adding an acetyl group.
Basic testing
Selected compounds are first tested in biochemical-pharmacological studies or experiments on cell cultures, isolated cells and isolated organs.
The toxicity study evaluates the following parameters:
- Toxicity during short-term and long-term use;
- The possibility of genetic damage (genotoxicity, mutagenicity);
- Possibility of tumor development (oncogenicity and carcinogenicity);
- Possibility of giving birth to a sick fetus (teratogenicity).
In animals, the compounds under study are also tested for absorption, distribution, metabolism, and excretion (pharmacokinetics).
Entering the market
Clinical testing involves several phases, which the infographic illustrates. First, new drugs are tested on healthy individuals to determine if the effects found in animal tests are observed in humans and to identify dose-effect relationships.
The decision to approve a new drug is made by the national regulatory agency (FDA). Applicants (pharmaceutical companies) submit to the regulatory body a complete set of preclinical and clinical trial documentation in which the efficacy and safety data obtained meet the established requirements and the intended form of the product (tablets, capsules, etc.)
The drug continues to be monitored as it is distributed. A final judgment on the benefit-risk ratio of a new drug can be made only on the basis of long-term experience of its use. This is how the therapeutic value of a new drug is determined.
In various cases, the process of developing a new drug from idea to implementation takes approximately 5 to 18 years. The total cost of development, including drugs that have not reached the market, often exceeds $1 billion (up to $2.5 billion on average).