Overview of drug discovery Flashcards
The history, economics and risks of drug discovery
History:
Drug discovery has a long history, dating back to the use of traditional medicines by ancient civilizations. The modern era of drug discovery began in the late 19th century with the isolation of morphine and other alkaloids from opium, followed by the discovery of penicillin in the 1920s. Since then, advances in technology, such as high-throughput screening and combinatorial chemistry, have dramatically accelerated the drug discovery process.
Economics:
Drug discovery is a costly and time-consuming process, with estimated costs ranging from hundreds of millions to billions of dollars per drug. The high costs are due to the extensive research and development required, including preclinical testing, clinical trials, and regulatory approval. These costs are typically borne by pharmaceutical companies, which are motivated by the potential profits from successful drugs. However, the high costs of drug development can lead to high drug prices and limited access to life-saving treatments, particularly in low- and middle-income countries.
Risks:
Drug discovery is also associated with significant risks, including high rates of failure and potential adverse effects on patients. The success rate for new drug development is low, with estimates suggesting that only 1 in 10,000 compounds tested will make it to market. This is due to a variety of factors, including the complexity of diseases, the difficulty in predicting drug efficacy and toxicity, and the high regulatory hurdles that drugs must clear before approval. Moreover, even approved drugs can have unexpected side effects, which can lead to serious health risks.
What is a lead compound
A lead compound is a chemical compound that shows promising activity against a biological target, such as an enzyme or receptor, in the drug discovery process. It is the first compound identified in a screening process that has the potential to become a drug candidate.
Lead compounds are typically identified through high-throughput screening (HTS), which involves testing large libraries of compounds against a target of interest. The compounds that show the most promising activity are then further optimized through a process called lead optimization, in which chemical modifications are made to the compound to improve its potency, selectivity, and other properties.
The ultimate goal of lead optimization is to develop a drug candidate that has optimal pharmacological properties, such as high potency, good bioavailability, and low toxicity, and that can progress through preclinical and clinical development to become a marketed drug.
In summary, a lead compound is an early-stage drug candidate that has shown promising activity against a biological target and is further optimized through lead optimization to improve its pharmacological properties and increase its chances of success in clinical trials.
What is high throughput screening
High throughput screening (HTS) is a method used in drug discovery to rapidly test large numbers of chemical compounds for their potential activity against a specific biological target, such as an enzyme or receptor.
HTS typically involves the use of robotics and automation to screen thousands to millions of compounds in a short period of time. The process begins with the creation of a library of compounds, which can include natural products, synthetic compounds, or a combination of both. The compounds are then transferred to microtiter plates, which are designed to hold small volumes of liquids.
The microtiter plates are then loaded onto automated screening systems, which use various assay formats to test the compounds for their activity against the biological target of interest. These assays can include enzyme assays, receptor binding assays, cell-based assays, or other types of assays that are designed to measure the activity of the target.
Once the screening is complete, the data is analyzed using computational methods to identify the compounds that show the most promising activity against the target. These “hits” are then further optimized through a process called lead optimization to improve their pharmacological properties and increase their chances of success in clinical trials.
HTS has revolutionized the drug discovery process by allowing researchers to rapidly screen large numbers of compounds and identify potential drug candidates more quickly and efficiently than traditional methods. However, it is important to note that HTS is just one step in the drug discovery process and must be followed by lead optimization, preclinical testing, and clinical trials to ensure the safety and efficacy of any potential drugs.
How drugs are discovered by both non-rational and rational approaches
Non-Rational Approach:
The non-rational approach to drug discovery involves the identification of natural products or synthetic compounds with potential biological activity through screening of large libraries of compounds. This approach is sometimes referred to as a “serendipitous” approach because it relies on chance discoveries.
Examples of non-rational approaches to drug discovery include the discovery of penicillin from a mold culture, the identification of the anticancer agent Taxol from the Pacific yew tree, and the discovery of the painkiller aspirin from willow bark.
Rational Approach:
The rational approach to drug discovery involves the use of knowledge about the structure and function of biological targets to design compounds that specifically interact with and modulate the target. This approach is sometimes referred to as a “structure-based” approach.
The rational approach to drug discovery involves several steps, including target identification, target validation, lead discovery, lead optimization, preclinical testing, and clinical trials.
Target identification involves the identification of a specific biological target, such as an enzyme or receptor, that is involved in a particular disease or disorder. Target validation involves demonstrating that the target is a valid target for drug development and that modulation of the target can lead to a therapeutic effect.
Lead discovery involves the identification of compounds that show potential activity against the target, often through high-throughput screening. Lead optimization involves the further development of the lead compound to improve its pharmacological properties, such as potency, selectivity, and bioavailability.
The process of drug discovery and development
Target identification and validation: This stage involves identifying a specific biological target, such as an enzyme or receptor, that is involved in a particular disease or disorder. Once a target is identified, it must be validated to ensure that it is a suitable target for drug development and that modulation of the target can lead to a therapeutic effect.
Lead discovery and optimization: Once a target is validated, the next step is to identify lead compounds that show potential activity against the target. This is often done through high-throughput screening of large libraries of compounds. The lead compounds are then optimized through a process called lead optimization to improve their potency, selectivity, and other pharmacological properties.
Preclinical testing: Once a lead compound is identified and optimized, it must be tested in preclinical studies to evaluate its safety, pharmacokinetics, and efficacy in animal models. These studies help to identify potential toxicity and other safety issues that need to be addressed before the compound can progress to human trials.
Investigational New Drug (IND) application: If the preclinical studies are successful, the next step is to submit an IND application to the regulatory authorities (e.g. FDA). This application includes data from the preclinical studies and outlines the proposed clinical development plan for the drug candidate.
Clinical trials: Clinical trials are conducted in three phases, each with its own specific objectives and requirements:
Phase 1 trials: These trials involve a small number of healthy volunteers and are designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of the drug candidate.
Phase 2 trials: These trials involve a larger number of patients and are designed to evaluate the efficacy of the drug candidate and to further assess its safety.
Phase 3 trials: These trials involve an even larger number of patients and are designed to confirm the efficacy and safety of the drug candidate in a larger population.
The impact of Precision Medicine on drug discovery
Targeted therapies: Precision medicine has led to the identification of new drug targets that are specific to certain genetic mutations or other molecular abnormalities. This has led to the development of targeted therapies that can more effectively treat certain diseases.
Personalized medicine: Precision medicine has also enabled the development of personalized medicine, which involves tailoring treatment to individual patients based on their unique genetic makeup, environmental factors, and lifestyle. This approach can improve treatment outcomes and reduce the risk of adverse events.
Biomarker discovery: Precision medicine has also led to the discovery of new biomarkers, which are indicators of disease or treatment response. Biomarkers can be used to identify patients who are most likely to respond to a particular treatment, allowing for more effective and efficient drug development.
Big data and artificial intelligence: Precision medicine generates large amounts of data, including genomic data, clinical data, and patient-reported outcomes. This data can be analyzed using artificial intelligence and machine learning algorithms to identify new drug targets and predict treatment outcomes.
identify solid phase peptide synthesis
Immobilization of the starting material: The starting material is first attached to a solid support, usually a polymer resin, which is insoluble in the solvents used in the reaction. This ensures that the reaction occurs only on the solid support, making it easier to purify the desired product.
Stepwise assembly of the molecule: The molecule is built up stepwise, one amino acid or nucleotide at a time. Each step involves the addition of a protected monomer to the growing chain, which is still attached to the solid support. The protecting groups are then removed to reveal the functional groups required for the next step.
Cleavage from the solid support: After the molecule has been fully assembled, it is cleaved from the solid support. This can be done by treatment with an appropriate cleavage agent that breaks the bond between the molecule and the solid support.
Purification and characterization: The cleaved product is then purified using techniques such as chromatography or crystallization, and its identity is confirmed using spectroscopic techniques like NMR, IR, or mass spectrometry.
Solid peptide synthesis
Selection of solid support: The first step in solid phase synthesis is the selection of an appropriate solid support. The most commonly used solid supports are polystyrene resins, which have functional groups that allow for the attachment of the first amino acid in the tripeptide.
Attachment of first amino acid: The first amino acid in the tripeptide is attached to the solid support using a linker molecule. The linker molecule must be stable under the reaction conditions and have a functional group that can react with the amino acid.
Protection of functional groups: To prevent unwanted side reactions, the functional groups on the amino acids are protected using appropriate protecting groups. Commonly used protecting groups include t-butyloxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc).
Stepwise assembly of the tripeptide: The tripeptide is assembled stepwise by adding each protected amino acid to the growing chain. After each addition, the protecting group is removed to expose the next reactive functional group.
Cleavage from the solid support: Once the tripeptide has been fully assembled, it is cleaved from the solid support using an appropriate cleavage reagent. This reaction removes the linker molecule and any protecting groups that are still present.
Purification and characterization: The final step is to purify the cleaved tripeptide and characterize it using spectroscopic techniques such as mass spectrometry and NMR.
Drug discovery methods
Natural product isolation: This involves the extraction and purification of compounds from natural sources such as plants, animals, and microorganisms. Once a bioactive compound is identified, it is further purified and studied to determine its pharmacological properties. An example of a drug discovered through natural product isolation is the antibiotic penicillin, which was isolated from a strain of Penicillium fungus.
High-throughput screening: This involves the testing of a large library of compounds for their ability to bind to a target receptor or enzyme. The compounds that show the most promising activity are then further studied and optimized to improve their pharmacological properties. An example of a drug discovered through high-throughput screening is sildenafil (Viagra), which was originally developed as a treatment for hypertension but was found to be more effective at treating erectile dysfunction.
Rational drug design: This involves the use of computational methods and structural information to design molecules that specifically interact with a target receptor or enzyme. The designed molecules are then synthesized and tested for their pharmacological properties. An example of a drug discovered through rational drug design is the HIV protease inhibitor, lopinavir, which was designed based on the crystal structure of the HIV protease enzyme.
Serendipity: This involves the accidental discovery of a drug while investigating other compounds or diseases. An example of a drug discovered through serendipity is the anti-inflammatory drug, aspirin, which was originally developed as a pain reliever but was found to also have anti-inflammatory properties.
