1.2 Drug sources and development
4 min read•august 16, 2024
Drug sources range from to . Plants, animals, and microorganisms provide valuable drugs like morphine and penicillin. Scientists also create by modifying natural products, and fully in labs.
Drug development is a complex process. It starts with discovering potential candidates through screening and optimization. Then, preclinical studies assess safety before test the drug in humans. Finally, regulatory agencies review data for approval.
Sources of Drugs
Natural and Semi-Synthetic Products
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- Natural products derived from plants, animals, and microorganisms serve as significant drug sources throughout history
- Morphine extracted from opium poppy plants
- Penicillin discovered in Penicillium mold species
- Semi-synthetic drugs created by chemically modifying natural products enhance efficacy or reduce side effects
- Heroin synthesized from morphine
- Ampicillin developed from penicillin
Synthetic and Biotechnology-Derived Compounds
- Synthetic compounds artificially created in laboratories through chemical synthesis
- Allow production of novel drugs with specific properties
- Designed to target specific biological pathways or receptors
- Biotechnology-derived substances produced using genetically engineered organisms or cell cultures
- (insulin)
- (trastuzumab)
- (CAR-T cell therapy)
Advanced Drug Discovery Methods
- techniques enable rapid synthesis and screening of large compound libraries
- Increases potential for discovering new drug candidates
- Allows for systematic exploration of chemical space
- identifies new therapeutic uses for existing drugs
- Significantly reduces development time and costs
- Examples include sildenafil (Viagra) originally developed for angina, repurposed for erectile dysfunction
Drug Development Stages
Drug Discovery and Optimization
- Drug discovery involves identifying potential drug candidates through various methods
- assesses compound interactions with specific molecular targets
- evaluates compound effects on cellular or organismal phenotypes
- utilizes structural information to design molecules
- refines promising drug candidates
- Improves potency, selectivity, and pharmacokinetic properties
- Involves iterative cycles of chemical modification and testing
Preclinical Studies and Regulatory Submission
- Preclinical studies assess safety and efficacy of drug candidates
- evaluate cellular effects and mechanism of action
- assess , toxicology, and efficacy
- application submitted to regulatory agencies
- Seeks approval for human clinical trials
- Includes preclinical data, manufacturing information, and clinical trial protocols
Clinical Trials and Drug Approval
- evaluate safety and pharmacokinetics
- Conducted in small groups of healthy volunteers or patients
- Determine safe dosage range and identify side effects
- assess efficacy and optimal dosing
- Involve larger groups of patients with the target disease
- Evaluate drug effectiveness and further assess safety
- confirm efficacy and safety on a large scale
- Multicenter studies comparing drug to existing treatments or placebos
- Generate data for statistical analysis of drug benefits and risks
- or submitted for marketing approval
- Comprehensive review by regulatory agencies ()
- Evaluation of safety, efficacy, and manufacturing quality
Drug Candidate Identification
High-Throughput Screening (HTS)
- HTS enables rapid testing of large compound libraries against specific targets or cellular assays
- Automated liquid handling systems and robotic platforms increase efficiency
- Miniaturization of assays reduces costs and sample requirements
- crucial for successful HTS campaigns
- Optimize for sensitivity, specificity, and reproducibility
- Examples include fluorescence-based assays and cell-based reporter systems
Computational Methods in Drug Discovery
- and predict binding affinity and interactions
- Structure-based virtual screening utilizes 3D protein structures
- Ligand-based approaches use known active compounds as templates
- and analyze large datasets
- Identify patterns leading to novel drug candidates
- Examples include deep learning models for predicting drug-target interactions
- Structure-based drug design utilizes 3D protein structures
- Guide design and optimization of potential drug molecules
- Examples include fragment-based drug design and de novo drug design
Quantitative Approaches and Cheminformatics
- models predict biological activity
- Based on chemical structures and physicochemical properties
- Aid in selecting promising candidates for further testing
- tools manage, analyze, and visualize chemical databases
- Facilitate identification of potential drug candidates
- Examples include molecular fingerprints and chemical similarity searches
Intellectual Property in Drug Development
Patent Types and Protection
- Patents provide exclusive rights for limited periods (typically 20 years from filing date)
- Incentivize pharmaceutical companies to invest in drug development
- Allow recouping of substantial costs associated with R&D
- Different patent types in drug development
- protect new chemical entities
- cover new therapeutic applications
- protect novel drug delivery systems
Patent Strategies and Extensions
- Patent exclusivity periods can be extended through various mechanisms
- Pediatric exclusivity encourages drug testing in children
- Orphan drug designation promotes research for rare diseases
- Patent strategies maximize protection and extend market exclusivity
- Filing multiple related patents (patent families)
- Continuation applications to cover additional aspects of inventions
Regulatory Framework and International Considerations
- in the United States balances innovation and generic competition
- Provides patent term restoration for time lost during regulatory review
- Establishes framework for abbreviated new drug applications (ANDAs)
- International patent laws and agreements facilitate global protection
- enables filing in multiple countries
- Regional patent systems (European Patent Office) streamline protection across member states
Key Terms to Review (52)
Adverse Effects: Adverse effects are unwanted or harmful reactions that occur in response to a drug or treatment, often limiting its use. These effects can range from mild side effects to severe complications, influencing the drug's therapeutic profile and patient safety. Understanding adverse effects is crucial throughout drug development, from initial sourcing and testing to clinical trials and market approval, and also impacts how drugs interact with receptors and each other.
Animal Models: Animal models are living organisms, typically non-human animals, used in research to study biological processes and diseases. These models help researchers understand the effects of drugs, test new therapies, and explore disease mechanisms in a controlled environment that closely mimics human conditions.
Artificial Intelligence: Artificial intelligence (AI) refers to the simulation of human intelligence in machines that are programmed to think, learn, and problem-solve like humans. In drug sources and development, AI plays a crucial role by analyzing vast amounts of data, identifying potential drug candidates, and predicting their effectiveness, significantly speeding up the discovery process while reducing costs and risks associated with traditional methods.
Assay Development: Assay development is the process of creating a reliable and efficient method for measuring the biological activity, potency, or pharmacological effects of a substance, often a drug candidate. This process is crucial in drug discovery as it allows researchers to evaluate the efficacy and safety of compounds before advancing them to clinical trials. Developing assays helps in identifying lead compounds from various sources and optimizing their therapeutic potential.
Bioavailability: Bioavailability refers to the proportion of a drug that enters the systemic circulation when introduced into the body and is available for therapeutic effect. It is influenced by factors such as the route of administration, formulation of the drug, and individual patient characteristics, making it a crucial aspect of pharmacology, drug development, and therapeutic effectiveness.
Biologics License Application (BLA): A Biologics License Application (BLA) is a submission to the U.S. Food and Drug Administration (FDA) that requests permission to introduce, or deliver for introduction, a biologic product into interstate commerce. This application is critical for ensuring the safety, purity, and potency of biologics, which include a wide range of products such as vaccines, blood components, and gene therapies. The BLA process involves rigorous testing and evaluation of the biologic's effectiveness and compliance with regulatory standards.
Biotechnology-derived compounds: Biotechnology-derived compounds are substances produced through biotechnological processes, including the manipulation of living organisms or their components. These compounds include proteins, nucleic acids, and small molecules, which are generated using techniques such as genetic engineering, fermentation, and cell culture. The significance of these compounds lies in their ability to lead to new drug development and therapies that can target specific diseases with precision.
Cheminformatics: Cheminformatics is a field that combines chemistry and computer science to analyze chemical data and manage chemical information. It plays a crucial role in drug discovery and development by enabling researchers to utilize computational tools for molecular modeling, data mining, and the visualization of chemical compounds. By leveraging cheminformatics, scientists can better understand the relationships between chemical structure and biological activity, facilitating the design of new drugs.
Clinical trials: Clinical trials are systematic studies conducted to evaluate the safety and effectiveness of new drugs or treatments in humans. These trials are essential in the drug development process, providing crucial data that guides regulatory approvals and clinical practice.
Combinatorial Chemistry: Combinatorial chemistry is a method used in drug discovery that enables the rapid synthesis and testing of a large number of chemical compounds. This technique allows scientists to create libraries of diverse molecules, which can then be screened for biological activity, significantly speeding up the process of identifying potential new drugs. It harnesses the power of parallel synthesis and high-throughput screening to streamline the development of pharmaceutical agents.
Composition of Matter Patents: Composition of matter patents are a type of intellectual property protection granted for inventions that consist of a combination of ingredients or components. These patents are essential in the pharmaceutical and chemical industries, as they safeguard the specific formulations of drugs or materials, ensuring that inventors can capitalize on their innovative combinations without fear of infringement from competitors.
Discovery phase: The discovery phase is the initial stage of drug development where potential therapeutic compounds are identified and evaluated for their biological activity and safety. This phase encompasses various activities including target identification, lead compound discovery, and optimization of chemical structures to enhance efficacy and minimize toxicity, laying the groundwork for further drug development.
Distillation: Distillation is a physical separation process that involves heating a liquid to create vapor and then cooling the vapor to form a liquid again. This method is commonly used to purify or separate components of a mixture based on their different boiling points, making it essential in the extraction and development of various drugs from natural sources or synthetic processes.
Drug Repurposing: Drug repurposing is the process of finding new therapeutic uses for existing drugs that are already approved for other medical conditions. This approach can significantly reduce the time and cost associated with drug development, as these medications have already undergone extensive safety and efficacy evaluations. It highlights the potential for existing drugs to address unmet medical needs, expanding their therapeutic applications beyond their original indications.
EMA: EMA stands for the European Medicines Agency, which is responsible for the scientific evaluation, supervision, and safety monitoring of medicines in the European Union. This agency plays a critical role in drug approval and regulation, overseeing clinical trials and ensuring that drugs meet high standards of quality and safety before they reach the market. The EMA's functions extend beyond approval, as it continuously monitors drug safety through pharmacovigilance, making it essential to the entire lifecycle of pharmaceuticals.
Extraction: Extraction is the process of isolating active compounds from natural sources, such as plants, animals, or minerals, for the purpose of drug development. This technique is vital in pharmacology as it enables scientists to obtain the necessary substances that can be used in formulating medications, leading to advancements in therapeutic options. By using various methods of extraction, researchers can identify, isolate, and concentrate these bioactive compounds, which is essential for understanding their pharmacological properties and potential applications.
FDA: The FDA, or Food and Drug Administration, is a federal agency of the United States Department of Health and Human Services responsible for protecting public health by regulating food, drugs, medical devices, and cosmetics. Its role is crucial throughout the drug development process, ensuring that drugs are safe and effective before they reach the market. The FDA oversees the entire lifecycle of drugs, from their initial discovery and development to their clinical trials and post-marketing surveillance.
Formulation Patents: Formulation patents are legal protections granted for the specific combinations and processes used to create pharmaceutical formulations, which include the active ingredients, excipients, and the method of preparation. These patents play a crucial role in drug development by safeguarding innovations in how drugs are formulated and delivered, thus ensuring that companies can invest in research and development without immediate competition from generic manufacturers. A strong formulation patent can provide a competitive advantage and secure a market position for the drug product.
Gene therapies: Gene therapies are medical treatments that involve altering the genes inside a patient's cells to treat or prevent disease. This innovative approach aims to correct defective genes responsible for disease development, potentially offering permanent solutions rather than temporary relief. By introducing, removing, or altering genetic material, gene therapies can address a wide range of conditions, including genetic disorders, some cancers, and viral infections.
Hatch-Waxman Act: The Hatch-Waxman Act, formally known as the Drug Price Competition and Patent Term Restoration Act of 1984, is a significant piece of legislation that aimed to balance the interests of pharmaceutical innovation and generic drug market entry. It established a streamlined process for generic drug approval and provided patent extensions for brand-name drugs, thereby promoting competition while ensuring that brand-name manufacturers are incentivized to invest in new drug development.
High-throughput screening (HTS): High-throughput screening (HTS) is a process used in drug discovery that allows researchers to quickly conduct millions of chemical, genetic, or pharmacological tests. This technology is crucial as it accelerates the identification of potential drug candidates by rapidly evaluating a vast library of compounds for their biological activity against specific targets. HTS significantly enhances the efficiency of drug development by streamlining the early stages of the process.
In Vitro Studies: In vitro studies refer to experiments conducted in a controlled environment outside of a living organism, often using cells, tissues, or biological molecules in lab settings. These studies are crucial for understanding drug interactions, biological mechanisms, and toxicity without the complexities and ethical concerns associated with in vivo studies. They provide valuable preliminary data in the early stages of drug development and are essential for assessing how drugs will be absorbed in the body.
Investigational New Drug (IND): An Investigational New Drug (IND) is a pharmaceutical agent that is being tested for safety and efficacy in clinical trials but has not yet been approved by regulatory authorities for general use. The IND designation allows the drug to be used in clinical studies to gather data on its effectiveness, safety, and optimal dosing, all crucial steps in the drug development process.
Lead Optimization: Lead optimization is a crucial stage in drug discovery where potential drug candidates (leads) are refined and improved to enhance their efficacy, selectivity, and safety profiles before advancing to clinical trials. This process involves iterative testing and modification of chemical structures to identify the most promising compounds that can effectively target specific diseases while minimizing adverse effects. Lead optimization bridges the gap between initial lead identification and the development of a viable drug candidate.
Machine Learning: Machine learning is a subset of artificial intelligence that involves the use of algorithms and statistical models to enable computers to improve their performance on a specific task through experience. This technology plays a critical role in drug discovery and development by analyzing large datasets to identify potential drug candidates, predict their efficacy, and streamline the research process.
Method of Use Patents: Method of use patents are legal protections granted for a specific way of using a known compound, drug, or product, allowing the patent holder exclusive rights to that method. These patents are crucial in the pharmaceutical industry as they can cover novel applications of existing drugs, thereby extending market exclusivity and encouraging further research and development in drug therapies. By securing these patents, companies can differentiate their products and ensure that they can recoup their investments in developing new uses for established medications.
Molecular docking: Molecular docking is a computational technique used to predict the preferred orientation of one molecule, typically a drug or ligand, when it binds to a target protein. This process helps researchers understand the interactions between molecules, which is crucial for drug design and development. By simulating how different compounds fit into specific binding sites of proteins, molecular docking aids in identifying potential new drugs and optimizing existing ones.
Monoclonal antibodies: Monoclonal antibodies are laboratory-made molecules engineered to bind to specific antigens in the body, acting as a targeted therapy for various diseases. These antibodies are produced by identical immune cells, cloned from a unique parent cell, ensuring that they all target the same antigen. Their precision allows them to play critical roles in diagnostics, treatment of cancers, autoimmune diseases, and as part of immunotherapy strategies.
Natural Products: Natural products are chemical compounds or substances produced by living organisms, including plants, animals, and microorganisms. They play a crucial role in drug discovery and development, as many pharmaceuticals are derived from these compounds, showcasing their importance in creating effective therapeutic agents.
New Drug Application (NDA): A New Drug Application (NDA) is a formal proposal submitted to the FDA for the approval of a new pharmaceutical product. This application includes comprehensive data on the drug's safety, efficacy, and manufacturing processes, which are critical for regulatory review and assessment. The NDA is an essential step in the drug development process, as it marks the transition from clinical trials to potential market availability.
Over-the-Counter Drugs: Over-the-counter drugs (OTC) are medications that can be purchased without a prescription, allowing consumers to treat minor health issues at their discretion. These drugs are typically deemed safe and effective for public use when consumers follow the instructions on the label. OTC drugs are an essential part of healthcare, as they provide convenient access to relief for common ailments and reduce the burden on healthcare providers.
Patent Cooperation Treaty (PCT): The Patent Cooperation Treaty (PCT) is an international treaty that allows inventors and companies to file a single patent application, which can then be recognized in multiple member countries. This streamlines the process of seeking patent protection across different jurisdictions and fosters global innovation by simplifying the patent application process, especially for pharmaceuticals and biotechnology products.
Paul Ehrlich: Paul Ehrlich was a pioneering German scientist known for his contributions to immunology and chemotherapy, particularly in the development of the first effective treatment for syphilis. His innovative ideas about using chemical compounds to target specific pathogens laid the groundwork for modern pharmacology and drug development.
Pharmacokinetics: Pharmacokinetics refers to the study of how the body absorbs, distributes, metabolizes, and excretes drugs over time. It encompasses the processes that determine the concentration of a drug in the bloodstream and its effects on the body, making it essential for understanding drug action and optimizing therapeutic regimens.
Phase I Clinical Trials: Phase I clinical trials are the first stage of testing a new drug or treatment in humans, primarily focusing on assessing safety, tolerability, and pharmacokinetics. This phase typically involves a small group of healthy volunteers or patients and aims to determine the appropriate dosage and identify any side effects, laying the groundwork for subsequent phases of clinical development.
Phase II Clinical Trials: Phase II clinical trials are a crucial stage in the drug development process, focusing on evaluating the efficacy and side effects of a drug after it has passed initial safety assessments in Phase I. These trials involve a larger group of participants than Phase I, typically ranging from 100 to 300 subjects, and are designed to gather more detailed information on how well the drug works for its intended purpose while continuing to monitor safety. This phase is essential in determining whether a drug should proceed to more extensive testing in Phase III, where it is compared against standard treatments.
Phase III Clinical Trials: Phase III clinical trials are large-scale studies conducted to evaluate the effectiveness and safety of a new drug or treatment in comparison to standard treatments. These trials involve thousands of participants and are critical for determining whether a drug can be approved for general use, as they provide substantial data on the drug's benefits and risks in diverse populations.
Phenotypic Screening: Phenotypic screening is a method used in drug discovery to evaluate the biological effects of compounds on living organisms or cells by observing the resulting phenotypes. This approach allows researchers to identify potential drug candidates based on their ability to produce desired effects, rather than relying solely on knowledge of molecular targets. By focusing on the observable traits or behaviors, phenotypic screening facilitates the discovery of novel therapeutic agents and enhances our understanding of disease mechanisms.
Plant-based drugs: Plant-based drugs are pharmaceutical compounds derived from various parts of plants, including leaves, roots, flowers, and bark. These drugs have been used for centuries in traditional medicine and have paved the way for modern pharmacology by providing a natural source of therapeutic agents that can treat a range of medical conditions.
Post-marketing surveillance: Post-marketing surveillance refers to the ongoing monitoring of the safety and effectiveness of a drug after it has been approved for public use. This process is crucial as it helps identify any adverse drug reactions or side effects that may not have been evident during clinical trials. It ensures that any risks associated with a drug are continuously assessed, allowing for timely updates to prescribing information and informing healthcare professionals and patients about potential safety concerns.
Preclinical Testing: Preclinical testing is a crucial phase in drug development where potential new drugs are evaluated for safety, efficacy, and pharmacokinetics before being tested in humans. This stage typically involves laboratory experiments and animal studies to gather essential data about the drug's effects, side effects, and optimal dosing. The results from preclinical testing help determine whether a drug candidate is suitable for progression to clinical trials, ensuring that only the most promising compounds are tested in human subjects.
Prescription drugs: Prescription drugs are medications that legally require a physician's authorization for their purchase and use. These drugs are typically regulated due to their potential for abuse, serious side effects, or the need for a healthcare professional's guidance in their administration. They play a critical role in the treatment of various medical conditions and are developed through rigorous processes involving research, testing, and regulatory approval.
Quantitative Structure-Activity Relationship (QSAR): Quantitative Structure-Activity Relationship (QSAR) is a mathematical approach used in medicinal chemistry to predict the biological activity of compounds based on their chemical structure. By correlating the molecular features of compounds with their observed effects, researchers can identify which structural elements contribute to desired pharmacological activities, aiding in drug design and development.
Rational Drug Design: Rational drug design is a systematic approach to developing new medications by using the knowledge of biological mechanisms and molecular structures to create compounds that can interact effectively with specific targets in the body. This method leverages information about the structure and function of biological molecules, particularly proteins and enzymes, to design drugs that are more effective and have fewer side effects. By understanding how drugs bind to their targets at a molecular level, scientists can make informed choices that enhance therapeutic outcomes.
Recombinant Proteins: Recombinant proteins are proteins that are engineered through the process of recombinant DNA technology, where DNA sequences from different sources are combined to produce desired proteins in host organisms. This technique allows for the mass production of proteins that can be used in therapeutics, diagnostics, and research, making it a pivotal advancement in biotechnology and pharmaceutical development.
Semi-synthetic drugs: Semi-synthetic drugs are medications that are chemically modified from their natural counterparts, combining elements from both natural and synthetic sources. This process allows for the enhancement of certain properties of the original compound, such as efficacy and stability, while often maintaining the therapeutic benefits. These drugs are important in drug development as they offer a balance between the availability of natural products and the precision of synthetic chemistry.
Sir James Black: Sir James Black was a renowned Scottish pharmacologist and Nobel Prize winner, best known for his pioneering work in drug development, particularly in the design of beta-blockers and H2 receptor antagonists. His innovative approaches in creating medications revolutionized the treatment of cardiovascular diseases and gastric conditions, significantly impacting pharmaceutical science and therapy.
Synthetic compounds: Synthetic compounds are chemical substances that are artificially created through chemical processes, rather than being derived from natural sources. These compounds play a crucial role in drug development, offering the ability to modify molecular structures to enhance therapeutic effects, improve safety, or reduce side effects. Their design allows for the creation of medications that can target specific biological pathways, leading to innovative treatments for various diseases.
Synthetic drugs: Synthetic drugs are man-made substances that mimic the effects of natural drugs or create entirely new pharmacological effects through chemical synthesis. They play a crucial role in modern medicine, as they can be specifically designed to target certain biological pathways, often resulting in more effective treatments with fewer side effects compared to their natural counterparts.
Target-based screening: Target-based screening is a method used in drug discovery to identify compounds that specifically interact with a chosen biological target, such as a protein or receptor. This approach allows researchers to focus on particular pathways or mechanisms of action, enhancing the efficiency of discovering new therapeutics. By selecting specific targets, scientists can streamline the drug development process and potentially identify candidates that have higher chances of success in clinical trials.
Therapeutic Index: The therapeutic index is a measure of the safety of a drug, calculated as the ratio between the toxic dose and the effective dose. A higher therapeutic index indicates a greater margin of safety, meaning that there is a larger difference between the dose that produces a desired therapeutic effect and the dose that causes toxicity.
Virtual Screening: Virtual screening is a computational technique used in drug discovery to identify potential drug candidates from large libraries of chemical compounds by predicting their interactions with target biological molecules. This approach accelerates the drug development process by narrowing down the vast number of compounds that can be tested experimentally, leading to more efficient resource allocation and reduced costs in developing new therapies.