Hit to Lead Activities and Lead Optimisation Flashcards
Understand the differences between hit compounds and suitable leads.
In drug discovery, hit compounds and suitable leads are two different types of molecules that are identified during the early stages of drug development.
Hit compounds are molecules that have been screened against a target in a high-throughput manner and have shown some level of activity or binding affinity. These compounds are typically identified through screening large libraries of compounds, and they may or may not have the characteristics required to become a drug. Hit compounds are often used as starting points for further optimization and development into drug candidates.
Suitable leads, on the other hand, are hit compounds that have been optimized through a series of medicinal chemistry processes to improve their potency, selectivity, pharmacokinetic properties, and safety profile. This optimization process involves modifying the chemical structure of the hit compound to enhance its activity against the target while minimizing any potential side effects. Suitable leads are more advanced in terms of drug development than hit compounds, and they have the potential to become viable drug candidates.
- Explain the key hit to lead activities and their role in optimisation of drug-like properties.
Medicinal chemistry: This involves modifying the chemical structure of the hit compound to improve its potency, selectivity, and other drug-like properties. Medicinal chemists use a range of techniques, such as structure-activity relationship (SAR) analysis, to identify key structural features of the hit compound that contribute to its activity and optimize them through iterative chemical modifications.
ADME (absorption, distribution, metabolism, and excretion) profiling: This involves assessing the pharmacokinetic properties of the hit compound to determine its suitability for further development. ADME profiling provides information on how the compound is absorbed, distributed, metabolized, and eliminated by the body, which can help medicinal chemists design compounds with optimal pharmacokinetic properties.
Safety profiling: This involves assessing the safety profile of the hit compound to identify any potential toxicities or adverse effects. Safety profiling includes in vitro and in vivo assays to evaluate the compound’s cytotoxicity, genotoxicity, and other safety parameters.
Pharmacology: This involves evaluating the hit compound’s activity in relevant biological assays and animal models to determine its efficacy and selectivity. Pharmacology data is used to guide the optimization process and ensure that the lead compound has the desired biological activity.
- Understand the key properties that should be considered for optimisation.
Potency: The potency of a lead compound refers to its ability to bind to the target and exert a biological effect at a low concentration. Increasing the potency of a lead compound is important to ensure that it has the desired biological activity and efficacy.
Selectivity: The selectivity of a lead compound refers to its ability to bind to the target of interest while minimizing its binding to other targets in the body. Increasing the selectivity of a lead compound can reduce the risk of off-target effects and improve its safety profile.
Pharmacokinetic properties: The pharmacokinetic properties of a lead compound refer to its absorption, distribution, metabolism, and excretion (ADME) characteristics. Optimizing the ADME properties of a lead compound is important to ensure that it can reach its target in the body, has a suitable half-life, and can be eliminated from the body in a safe and efficient manner.
Toxicity and safety profile: The toxicity and safety profile of a lead compound refer to its potential to cause adverse effects in the body. Optimizing the toxicity and safety profile of a lead compound is important to ensure that it has a favorable risk-benefit profile and can be safely administered to patients.
Chemical stability: The chemical stability of a lead compound refers to its ability to remain stable under storage and processing conditions. Optimizing the chemical stability of a lead compound is important to ensure that it can be manufactured and formulated into a dosage form for administration to patients.
Intellectual property: The intellectual property of a lead compound refers to its novelty and patentability. Optimizing the intellectual property of a lead compound is important to ensure that it has a competitive advantage in the market and can be protected by patents.
Learn the key characteristics of hit compounds and the chemical spaces covered by hit compounds.
Potency: Hit compounds must exhibit some degree of activity against the target, with potency typically in the low micromolar to high nanomolar range.
Selectivity: Hit compounds should exhibit some degree of selectivity for the target of interest, rather than binding to other proteins or cellular components.
Chemical tractability: Hit compounds must possess chemical properties that allow them to be modified and optimized through medicinal chemistry efforts. This includes good solubility, stability, and low toxicity.
Diversity: Hit compounds should represent a diverse set of chemical scaffolds, providing a range of structural starting points for optimization.
- Explain the criteria to move hit compounds to the lead optimisation phase.
Activity and selectivity: Hit compounds must show sufficient activity against the target of interest and exhibit some degree of selectivity to warrant further optimization efforts.
Chemical tractability: Hit compounds must possess chemical properties that allow for modification and optimization through medicinal chemistry. This includes good solubility, stability, and low toxicity.
ADME properties: Hit compounds must have favorable absorption, distribution, metabolism, and excretion (ADME) properties to be viable drug candidates. These properties can be assessed through in vitro and in vivo assays.
Intellectual property: Hit compounds must not infringe on existing patents or intellectual property rights.
Feasibility and novelty: Hit compounds must be feasible to synthesize on a large scale and have a reasonable chance of being developed into a novel drug.
Competitive landscape: Hit compounds should be evaluated in the context of the competitive landscape to determine if they have the potential to differentiate themselves from existing therapies.
Understand the druggability assessment processes that are routinely applied during the hit to lead
optimisation stage.
Lipophilicity and solubility assessment: Lipophilicity and solubility are crucial properties to evaluate during druggability assessment. Compounds with high lipophilicity may have poor solubility, which can limit their bioavailability. Lipophilicity and solubility can be evaluated through in vitro assays, such as octanol-water partition coefficient (logP) and aqueous solubility measurements.
Pharmacokinetics evaluation: Compounds with favorable pharmacokinetic properties have a better chance of success in drug development. Pharmacokinetic parameters, such as half-life, clearance, volume of distribution, and oral bioavailability, can be evaluated through in vitro and in vivo assays.
Structural analysis: Structural analysis of a compound can provide insight into its potential druggability. Compounds with favorable structural properties, such as size, shape, and hydrogen bonding capacity, are more likely to interact with target proteins.
Binding affinity: Compounds with high binding affinity to the target protein are more likely to exhibit efficacy in vivo. Binding affinity can be evaluated through in vitro assays, such as surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC).
Safety and toxicity evaluation: Compounds must also be evaluated for safety and toxicity during druggability assessment. In vitro assays, such as hERG channel inhibition and cytotoxicity assays, can be used to assess the safety of a compound.
ADME profiling: ADME profiling evaluates the absorption, distribution, metabolism, and excretion of a compound. This can be evaluated through in vitro and in vivo assays, such as Caco-2 permeability, plasma protein binding, and metabolite identification studies.
- Explain the optimisation cycle and the pros and cons of different optimisation strategies.
The optimization cycle in drug discovery involves iterative cycles of designing and synthesizing new compounds, testing them for activity and selectivity, and modifying them based on the results. The goal is to improve the potency, selectivity, and pharmacokinetic properties of the lead compound while minimizing toxicity.
There are several optimization strategies that can be employed during the optimization cycle, including:
Structure-activity relationship (SAR) analysis: SAR analysis involves evaluating the structure-activity relationships of compounds to identify key structural features that contribute to potency and selectivity. Medicinal chemists can then modify the compound to optimize these features.
Scaffold hopping: Scaffold hopping involves replacing the core structure of a compound with a structurally distinct scaffold while retaining key pharmacophores. This strategy can help address issues of toxicity or low selectivity.
Bioisosterism: Bioisosterism involves replacing a functional group or atom in a compound with a structurally similar group or atom that has similar physicochemical properties. This strategy can help improve potency or selectivity while maintaining chemical tractability.
Fragment-based drug design: Fragment-based drug design involves identifying small, low-affinity compounds that bind to the target protein and using them as a starting point for building larger, more potent compounds. This strategy can help optimize binding affinity while minimizing toxicity.
Pros and cons of different optimization strategies:
Each optimization strategy has its advantages and disadvantages, and the choice of strategy depends on the specific characteristics of the lead compound and the target protein.
SAR analysis is a widely used optimization strategy that is relatively straightforward and effective. However, it can be time-consuming and may not address issues of toxicity or selectivity.
Scaffold hopping can be effective in addressing issues of toxicity or selectivity, but it can be challenging to find a suitable replacement scaffold, and the resulting compound may have reduced potency.
Bioisosterism can be effective in improving potency or selectivity while maintaining chemical tractability, but it can be challenging to find suitable bioisosteres, and the resulting compound may have reduced binding affinity.
Fragment-based drug design can be effective in optimizing binding affinity while minimizing toxicity, but it requires specialized expertise and can be expensive and time-consuming.
- Explain the optimisation cycle and the pros and cons of different optimisation strategies.
Structure-activity relationship (SAR) analysis: SAR analysis involves evaluating the structure-activity relationships of compounds to identify key structural features that contribute to potency and selectivity. Medicinal chemists can then modify the compound to optimize these features.
Scaffold hopping: Scaffold hopping involves replacing the core structure of a compound with a structurally distinct scaffold while retaining key pharmacophores. This strategy can help address issues of toxicity or low selectivity.
Bioisosterism: Bioisosterism involves replacing a functional group or atom in a compound with a structurally similar group or atom that has similar physicochemical properties. This strategy can help improve potency or selectivity while maintaining chemical tractability.
Fragment-based drug design: Fragment-based drug design involves identifying small, low-affinity compounds that bind to the target protein and using them as a starting point for building larger, more potent compounds. This strategy can help optimize binding affinity while minimizing toxicity.
Pros and cons of different optimization strategies:
Each optimization strategy has its advantages and disadvantages, and the choice of strategy depends on the specific characteristics of the lead compound and the target protein.
SAR analysis is a widely used optimization strategy that is relatively straightforward and effective. However, it can be time-consuming and may not address issues of toxicity or selectivity.
Scaffold hopping can be effective in addressing issues of toxicity or selectivity, but it can be challenging to find a suitable replacement scaffold, and the resulting compound may have reduced potency.
Bioisosterism can be effective in improving potency or selectivity while maintaining chemical tractability, but it can be challenging to find suitable bioisosteres, and the resulting compound may have reduced binding affinity.
Fragment-based drug design can be effective in optimizing binding affinity while minimizing toxicity, but it requires specialized expertise and can be expensive and time-consuming.
- Explain Lipinski’s rule of 5 and its role in design and development of orally bioavailable drugs.
It has a molecular weight of less than 500 Daltons.
It has no more than 5 hydrogen bond donors (such as NH or OH groups).
It has no more than 10 hydrogen bond acceptors (such as nitrogen or oxygen atoms).
Its calculated LogP (octanol-water partition coefficient) is less than or equal to 5.
Explain the key safety considerations during the lead optimisation process using appropriate case
studies.
Identification of toxicophores: Toxicophores are structural features of a molecule that are known to be associated with toxicity. Identification and elimination of toxicophores during the lead optimization process are critical to improving the safety profile of the compound. For example, the presence of electrophilic groups such as an aldehyde, ketone, or nitro group can lead to toxicity through the formation of reactive intermediates that can damage cellular macromolecules. Identification and elimination of these groups can improve the safety profile of the compound.
Optimization of pharmacokinetic properties: The pharmacokinetic properties of a compound, such as absorption, distribution, metabolism, and elimination, can significantly affect its safety profile. Optimization of pharmacokinetic properties, such as reducing the clearance rate or increasing plasma protein binding, can improve the safety profile of the compound. For example, the optimization of pharmacokinetic properties of the anticoagulant drug dabigatran has led to a reduction in bleeding events and improved its safety profile.
Prediction of off-target effects: Off-target effects can occur when a compound binds to unintended targets in the body, leading to adverse effects. Predicting and minimizing off-target effects during the lead optimization process is critical to improving the safety profile of the compound. For example, the antipsychotic drug risperidone was found to have off-target effects on the histamine H1 receptor, leading to weight gain and sedation. Subsequent lead optimization efforts led to the development of a more selective compound with reduced off-target effects.
Assessment of genotoxicity and carcinogenicity: The assessment of genotoxicity and carcinogenicity during the lead optimization process is critical to identifying compounds with potential long-term toxic effects. For example, the antidiabetic drug rosiglitazone was found to increase the risk of heart attacks and was withdrawn from the market due to concerns about its long-term safety.
