In this section we will briefly cover the history.

The history of drug discovery dates back to ancient times, where natural products were utilized for medicinal purposes.
However, the search for drug targets began to take shape only in the early 20th century as scientists gained a better understanding
of the molecular basis of diseases and the role of specific proteins in the development of certain conditions.
In 1905, John Langley introduced the concept of "receptive substances," proposing the receptor theory of drug action.
This research inspired subsequent investigations in medicinal chemistry and led to the development of novel concepts such as
ligand-receptor interaction. Paul Ehrlich expanded upon drug receptor theory and initiated the first rational development of synthetic
drugs through his concept of the "magic bullet." Ehrlich's goal was to develop drugs that could specifically target disease-causing
pathogens without harming healthy cells. This led to the creation of Salvarsan (also known as compound 606 or Arsphenamine), the
first effective treatment for syphilis, which marked the beginning of chemotherapy as a scientific discipline.
During the early stages of drug discovery, the tools available to chemists and the biological knowledge about potential
targets were limited. One of the major breakthroughs of that era was Alexander Fleming's discovery of penicillin in 1928 marked a
significant advancement in chemotherapy and led to the development of new antibiotics for treating bacterial infections. However the
target of penicillin was not discovered until several decades later.
The real progress in drug target discovery occurred in the 1950s and 1960s with the discovery of the structure and
function of enzymes and the development of the first enzyme-inhibiting drugs. During this period, hundreds of enzymes were
studied, eventually becoming important molecular targets for drug discovery. One such example is HMG-CoA reductase, an enzyme
involved in cholesterol synthesis, which became a drug target in the 1980s with the development of statins. Another example is
monoamine oxidase, an enzyme that breaks down neurotransmitters like serotonin and dopamine. Inhibitors of MAO were
developed in the 1960s and 1970s and are still used today as antidepressants.
Receptor pharmacology and the nature of druggability drove the research towards receptors, making them the most
popular targets for drug discovery. The development of β adrenergic receptor antagonists (beta blockers) is considered one of the
most significant contributions to clinical medicine and pharmacology in the 20th century.
Computers started to become integrated into drug development in the 1960s due to the need for more efficient ways to
store and analyze growing amounts of biological data. One of the first applications of computers was the analysis of molecular
structures. By this time, electron density maps of myoglobin, lysozyme, and other macromolecules had been generated by x-ray
crystallographers. The earliest computer representations of biological macromolecules can be dated as early 1960s. In 1971, the
Protein Data Bank was established with just two protein structures. The database started to grow exponentially during the 1980s
with the addition of numerous structures each year.
The development of gene cloning and advanced molecular biology techniques allowed for a more systematic and rational
approach to working on specific protein targets. This approach, called target-based drug discovery, was quickly adopted by many
pharmaceutical companies. Recombinant DNA technology made it possible to create new assays for a variety of molecular targets,
enabling rapid screening of large chemical libraries using purified recombinant proteins or engineered cell lines to discover new
pharmacologically active compounds, both synthetic and naturally occurring. Developments in combinatorial chemistry, assay
miniaturization, and robotic automation greatly facilitated the high-throughput screening in the 1990s. Molecular biology techniques
also led to the development of therapeutic biologics, including monoclonal antibodies that target specific proteins.
The late 1990s marked the beginning of the "omics revolution," a period of rapid advancement in high-throughput
technologies for analyzing DNA (genomics), RNA (transcriptomics), proteins (proteomics), and small molecules (metabolomics). The
launch of the Human Genome Project in 1990, completed in 2003, was a major milestone in the development of genomics.
Advances in genomics in the 2000s led to the discovery of new therapeutic targets for a wide range of diseases through genome-
wide association studies. For instance, a 2008 study identified recurring mutations in the IDH1 gene in glioblastoma that were
associated with increased survival. Similar mutations in the IDH2 gene were later identified in other cancers, leading to the creation
of drugs that target mutated IDH2.
The utilization of microarray technology in the late 1990s for transcriptomics allowed for drug-induced gene expression
profiling in cell lines and in vivo models to assess the biological effects of potential targets and predict therapeutic efficacy
beforehand. The omics revolution, which includes the rational design of small molecules, has also led to an increase in the
production of biopharmaceutical drugs, such as monoclonal antibodies, recombinant proteins, and nucleic acid-based drugs.
Recently, artificial intelligence has emerged as a groundbreaking technique for analyzing large amounts of
pharmacological data, leading to an increase in drug identification success rates. AI can learn from experimental data in biomedical
research to discover new rules for converting the data into understandable knowledge. Pharmaceutical companies are starting to
use AI to discover targets and improve the effectiveness of drug candidates, thereby reducing unnecessary testing and synthesis
and saving time and money.
AlphaFold, an AI-based tool for target discovery, was introduced in 2018 and uses deep learning techniques to predict the
3D structures of proteins. It has been hailed as a major breakthrough in the field of structural biology.
Another example of AI-based tools is PandaOmics, an automated platform launched in 2020 to accelerate and optimize
key steps in early drug discovery. PandaOmics combines bioinformatics methods with advanced multimodal deep learning
approaches for target identification.
Currently, AI-generated drugs are entering early clinical stages and we can expect AI to play a leading role in the drug
discovery and development process in the coming decade.
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