Overview of drug discovery Flashcards
Understand the drug discovery process and the challenges of each step.
Target Identification: This is the first step in the drug discovery process, where researchers identify a specific protein or gene that is involved in a disease. The challenge in this step is to identify a target that is specific to the disease and has minimal side effects.
Target Validation: Once a potential target has been identified, researchers need to validate its role in the disease. This involves confirming that the target is indeed involved in the disease and that inhibiting or activating it will have a therapeutic effect. The challenge in this step is to identify a target that is druggable and can be modulated by small molecules.
Lead Discovery: In this step, researchers use various methods to identify compounds that can bind to the target and modulate its activity. The challenge in this step is to identify compounds that have high potency, selectivity, and good pharmacokinetic properties.
Lead Optimization: Once a lead compound has been identified, researchers optimize its chemical structure to improve its potency, selectivity, and pharmacokinetic properties. The challenge in this step is to balance the need for improved properties with the need for a compound that can be synthesized and manufactured at scale.
Preclinical Testing: Once a lead compound has been optimized, it undergoes preclinical testing to assess its safety, efficacy, and pharmacokinetic properties in animal models. The challenge in this step is to ensure that the compound is safe and effective in animal models and that it has a clear path to clinical development.
Clinical Development: If a compound passes preclinical testing, it proceeds to clinical development, where it is tested in human trials. This involves three phases of clinical trials, where the compound is tested for safety, efficacy, and pharmacokinetic properties. The challenge in this step is to conduct rigorous and ethical clinical trials and to ensure that the compound has a clear path to regulatory approval.
Regulatory Approval: Once a compound has completed clinical trials, it undergoes regulatory review by the FDA or other regulatory agencies. The challenge in this step is to meet the regulatory requirements for safety, efficacy, and manufacturing quality.
Appreciate the involvement of different disciplines in the drug discovery
process.
Medicinal Chemistry: Medicinal chemists are involved in the design and synthesis of small molecules that can bind to specific targets and modulate their activity. They use their knowledge of organic chemistry to optimize the properties of the compounds, such as potency, selectivity, and pharmacokinetics.
Pharmacology: Pharmacologists study the effects of drugs on the body and the mechanisms by which they produce their effects. They use animal models and in vitro assays to test the efficacy and safety of potential drug candidates.
Biology: Biologists study the biology of the disease and the mechanisms by which potential drug targets are involved in the disease. They use various techniques, such as molecular biology, genetics, and cell biology, to identify and validate drug targets.
Computational Chemistry: Computational chemists use computational methods, such as molecular modeling and simulation, to predict the properties of potential drug candidates, such as binding affinity and pharmacokinetics.
Toxicology: Toxicologists study the toxic effects of drugs on the body and identify potential safety issues that may arise during drug development. They also develop strategies to minimize the toxicity of potential drug candidates.
Clinical Development: Clinical researchers design and conduct clinical trials to test the safety and efficacy of potential drug candidates in human subjects. They work closely with regulatory agencies to ensure that the trials are conducted ethically and according to regulatory requirements.
Manufacturing: Manufacturing experts develop scalable processes for synthesizing and manufacturing drug candidates in large quantities. They ensure that the processes meet quality and regulatory standards.
Understand the reasons behind the high attrition rate in drug discovery.
Safety Concerns: Safety is a major concern in drug discovery, and many potential drug candidates fail to reach the market due to safety issues. Safety concerns can arise due to toxicity, adverse reactions, or off-target effects.
Lack of Efficacy: Many potential drug candidates fail to show significant efficacy in preclinical or clinical studies. This can be due to poor target validation, inadequate potency, poor pharmacokinetic properties, or poor patient selection.
Manufacturing Challenges: Manufacturing challenges can arise during the drug discovery process, and many potential drug candidates fail to reach the market due to difficulties in scaling up the production of the drug.
Regulatory Hurdles: Regulatory hurdles can also prevent potential drug candidates from reaching the market. Regulatory agencies require extensive data on the safety and efficacy of a drug before it can be approved for marketing, and many potential drug candidates fail to meet these requirements.
High Development Costs: Drug discovery is an expensive process, and many potential drug candidates fail to reach the market due to high development costs. The cost of developing a new drug can be in the billions of dollars, and many companies cannot afford to invest in the development of a drug that is unlikely to reach the market.
Complexity of Diseases: The complexity of many diseases is another reason behind the high attrition rate in drug discovery. Diseases often involve multiple pathways and mechanisms, making it difficult to develop drugs that can effectively target all the components of the disease.
Explain the role of pharmacophore in hit identification and lead generation.
Hit Identification: During the hit identification stage, pharmacophores can be used to screen large chemical databases to identify compounds that possess the necessary chemical features to bind to a specific target. By using pharmacophores to filter out compounds that do not fit the necessary criteria, researchers can focus their efforts on a smaller subset of molecules that are more likely to be active.
Lead Generation: Once a hit compound has been identified, pharmacophores can be used to optimize the compound’s properties and to design new analogs with improved activity. By using the pharmacophore model of the hit compound as a template, medicinal chemists can modify the structure of the molecule to enhance its binding affinity, selectivity, and pharmacokinetic properties.
Pharmacophores can also be used to identify new targets for drug discovery. By comparing the pharmacophore of a known ligand for a specific target with the pharmacophore of other compounds, researchers can identify potential ligands that may bind to the same target. This approach is known as ligand-based virtual screening and is commonly used in drug discovery.
Learn the importance of ADME evaluation in the drug discovery process.
Identifying potential safety concerns: ADME evaluation helps to identify compounds that have potential safety concerns, such as poor absorption or distribution, metabolic instability, or toxicity. By identifying these issues early on in the drug discovery process, scientists can eliminate compounds that are unlikely to become safe and effective drugs, saving time and resources.
Optimizing pharmacokinetic properties: ADME evaluation can help scientists to optimize the pharmacokinetic properties of a drug, such as its absorption, distribution, and elimination from the body. This can improve the drug’s efficacy, reduce the risk of toxicity, and increase its half-life in the body, leading to less frequent dosing.
Supporting drug development: ADME evaluation provides important information that is required by regulatory agencies, such as the US Food and Drug Administration (FDA), to approve a drug for clinical trials and eventually for commercial use. ADME studies are typically conducted in the preclinical stages of drug development to support safety and efficacy studies.
Reducing attrition rates: ADME evaluation can help to reduce the attrition rates in drug discovery by identifying compounds that are unlikely to become safe and effective drugs early on in the drug discovery process. This can save time and resources, as well as reduce the number of animal studies required.
Understand the selection criteria for hit, lead and clinical candidate
compounds.
Hit selection criteria:
High potency: The compound should have a high affinity for the target protein, with an IC50 or Ki in the low micromolar or nanomolar range.
Selectivity: The compound should be selective for the target protein and not bind to off-target proteins or have non-specific effects.
Physicochemical properties: The compound should have favorable physicochemical properties, such as solubility, permeability, and stability, to ensure that it can reach the target in vivo.
Structural novelty: The compound should be structurally novel and not have been previously reported as a hit for the target.
Drug-likeness: The compound should have drug-like properties, such as low molecular weight, no reactive functional groups, and no structural alerts for toxicity.
Lead selection criteria:
Improved potency: The compound should have improved potency compared to the hit compound, with an IC50 or Ki in the low nanomolar or picomolar range.
Selectivity: The compound should maintain selectivity for the target protein and not bind to off-target proteins or have non-specific effects.
Physicochemical properties: The compound should have favorable physicochemical properties, such as solubility, permeability, and stability, to ensure that it can reach the target in vivo.
Pharmacokinetics: The compound should have favorable pharmacokinetic properties, such as half-life, clearance, and bioavailability, to ensure that it can be dosed effectively in vivo.
In vivo efficacy: The compound should demonstrate efficacy in animal models of the disease.
Clinical candidate selection criteria:
Safety: The compound should be safe for human use and not have any toxic or adverse effects.
Efficacy: The compound should demonstrate efficacy in human clinical trials.
Pharmacokinetics: The compound should have favorable pharmacokinetic properties, such as half-life, clearance, and bioavailability, to ensure that it can be dosed effectively in humans.
Formulation: The compound should be able to be formulated into a stable and effective dosage form for human use.
Intellectual property: The compound should have intellectual property protection and be commercially viable.
