What is a hit in drug development?
In drug development, a "hit" refers to a compound or molecule that shows promise during the initial stages of screening and testing for its ability to interact with a specific biological target, such as a protein associated with a disease. Hits are typically identified during high-throughput screening (HTS) processes where numerous compounds are evaluated for their biological activity or desired effects.
Assessing this "affinity" in drug development is crucial for understanding how well a drug interacts with its target, such as a receptor or enzyme. There are several technologies and methods employed in this process, including:
- Surface Plasmon Resonance (SPR): This real-time, label-free technology measures the binding interactions between molecules at a sensor surface. SPR can provide kinetic data and affinities by monitoring changes in refractive index as molecules bind or dissociate.
- Isothermal Titration Calorimetry (ITC): ITC directly measures the heat change associated with a binding event, allowing the determination of binding affinity, kinetics, and thermodynamic parameters (like enthalpy and entropy).
- Fluorescence Polarization (FP): This technique assesses binding interactions by measuring the change in polarization of fluorescently labeled molecules after they bind to a target. It can be used to estimate affinities and displacement events.
- Bio-Layer Interferometry (BLI): Similar to SPR, BLI measures the interference pattern of reflected light from a biosensor surface. It enables the assessment of binding kinetics and is often used for real-time monitoring of interactions.
- Radiolabeled Binding Assays: These assays utilize radioisotope-labeled compounds to study the competitive binding of drugs totarget proteins. Binding affinity is assessed based on the amount of radioactivity displaced by varying concentrations of compounds.
- Equilibrium Dialysis: This method evaluates the affinity of a drug for a target by measuring the concentration of a drug in two compartments separated by a membrane. It can help estimate the free versus bound drug concentration.
- Fluorescence Resonance Energy Transfer (FRET): FRET is used to study molecular interactions and can provide information about binding affinity. A donor and acceptor dye couple is used to detect proximity between a ligand and its target.
- Mass Spectrometry (MS): When coupled with techniques like affinity chromatography, mass spectrometry can quantify binding interactions and affinities by analyzing the mass of complexes formed during binding.
Each of these technologies has its advantages and limitations, and the choice often depends on the specific needs of the drug development process, including the nature of the target, the drug candidates being studied, and the required throughput and sensitivity of the assays. Often, multiple methods are used in parallel to gain a comprehensive understanding of drug-target interactions.
Once a hit is identified, it is subjected to further investigation to determine its efficacy, safety, pharmacokinetic properties, and potential for optimization. The process often involves lead optimization to enhance the hit's characteristics before advancing to more extensive preclinical and clinical testing. Hits are foundational to the drug discovery process, as they can potentially lead to the development of new therapeutic agents.
Lead Optimization
Lead optimization is a critical phase in the drug development process that occurs after the identification of potential drug candidates, referred to as "leads." This stage focuses on refining and improving these lead compounds to enhance their pharmacological properties, making them more effective, safer, and more suitable for development into a viable drug.
Key objectives of lead optimization include:
- Improving Efficacy: Enhancing the therapeutic activity of the lead compound against the target disease or condition.
- Enhancing Selectivity: Modifying the compound to increase its selectivity for the intended target while minimizing interactions with other proteins or biological pathways, which can help reduce side effects.
- Optimizing Pharmacokinetics: Improving the absorption, distribution, metabolism, and excretion (ADME) characteristics of the lead compound to ensure that it reaches the intended site of action at therapeutic levels and is eliminated appropriately from the body.
- Increasing Stability: Enhancing the chemical and physical stability of the compound to ensure that it retains its efficacy over time and under various conditions.
- Reducing Toxicity: Identifying and mitigating any potential toxic effects associated with the lead compound, improving its safety profile.
- Facilitating Formulation: Ensuring that the lead compound can be formulated into a delivery system (like tablets, injectables, etc.) that is feasible for clinical use.
The process of lead optimization is iterative and involves several rounds of chemical synthesis, biological testing, and computational modeling to evaluate the effects of modifications on the compound's properties.
Ultimately, the goal of lead optimization is to produce a lead candidate that demonstrates sufficient promise to progress into further phases of development, including preclinical and clinical testing. This stage is crucial for increasing the chances of successful drug development and commercial viability.
Pion Inc. has a long history of helping drug formulators in their drug development efforts with our T3 physchem platform for pKa and log P and log D determinations, our Rainbow in situ, fiber optic-based UV-vis, real-time concentration monitor for dissolution rates and flux studies, our flux platforms to assess membrane permeability, and our Pion Predictor Software – a tool to understand the oral drug absorption rate-limiting step and determine a compound's BCS Class.
Contact us today to learn more.
