Compound library
Compound Library
The compound or fragment library designed in PROTAC is an efficient collection of diverse chemical compounds utilized in drug discovery and other areas of chemistry like high-throughput screening to identify active compounds, or “hits,” that target biological systems. The quality and effectiveness of a chemical library play a crucial role in the success of drug discovery campaigns. In designing our chemical library, we adhere to universal standards used in drug discovery, repurposing, and hit identification, ensuring the following properties:
- Chemical Diversity
- Drug-Likeness
- Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Properties
- Scaffold Diversity and Novelty
- Fragment-Based Compounds
- Synthesis Accessibility and Scalability
- Chemical Stability
- Exclude Pan-Assay Interference Compounds (PAINS)
- Intellectual Property (IP) Freedom
- Balanced Physicochemical Properties
- Biological Relevance
- Quality Control and Curation
Chemical Diversity
- Structural diversity ensures a wide variety of molecular scaffolds, functional groups, and stereochemistry, which increases the likelihood of discovering effective compounds for various biological targets.
- Functional diversity encompasses a range of pharmacophoric features, including hydrogen bond donors and acceptors, hydrophobic moieties, and polar groups. These features interact with different binding sites on proteins and other targets.
- Chemical space coverage: The library should encompass a broad spectrum of chemical space while minimizing redundancy. We can fulfill the concept using molecular descriptors, fingerprints, and clustering techniques.
Drug -Likeness
- Lipinski’s Rule of Five compliance: To improve the chances of compounds being orally bioavailable, PROTAC’s library contains compounds with properties that generally follow Lipinski’s rules, such as:
- Molecular weight ≤ 500 Da
- LogP ≤ 5
- Hydrogen bond donors ≤ 5
- Hydrogen bond acceptors ≤ 10
- Veber’s Rule: Ensures flexibility and permeability, with parameters such as the number of rotatable bonds (≤ 10) and polar surface area (PSA ≤ 140 Ų).
Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) Properties
- Solubility: The compounds demonstrate good solubility in water or biological fluids, allowing for effective testing in biological assays.
- Permeability: The capability to cross cell membranes is crucial for accessing intracellular targets.
- Metabolic stability: The compounds have balanced metabolic stability and clearance, ensuring they remain in the body long enough to have an effect.
- Toxicity: The PROTAC library avoids compounds with known toxicophores—structures linked to toxicity—including mutagenic, carcinogenic, or teratogenic.
Scaffold Diversity and Novelty
- The chemical library consists of diverse chemical scaffolds (core structures) that expose various substituents. This design minimizes redundancy and enhances the exploration of different biological targets.
- Novel scaffolds are especially valuable for identifying drugs that target unique or previously undruggable sites. Additionally, the library includes compounds or fragments inspired by natural products, which are often more relevant to biological processes.
Fragment -Based Compounds
- Many libraries incorporate fragment-based drug design (FBDD) principles, where smaller, simpler molecules (fragments) with lower molecular weights (150–300 Da) are used. These fragments can bind efficiently to biological targets and serve as starting points for optimizing larger, more potent molecules.
- Fragments follow “Rule of Three” (MW ≤ 300 Da, H-bond donors ≤ 3, H-bond acceptors ≤ 3, and LogP ≤ 3).
Synthesis Accessibility and Scalability
- Compounds involved in PROTAC’s chemical library are easily synthesized or sourced in large quantities to facilitate follow-up testing, hit-to-lead development, and scale-up in drug discovery programs.
- Synthetic feasibility ensures that hits identified from screening can be modified and optimized through medicinal chemistry without significant synthetic challenges.
Chemical Stability
- Compounds in the PROTAC’s library are chemically stable, avoiding degradation over time or under assay conditions (e.g., stability in air, light, water, and various solvents).
- Stability against hydrolysis, oxidation, and racemization is important for maintaining library quality during storage and screening.
Exclude Pan-Assay Interference Compounds (PAINS)
- The PROTAC’s library avoids PAINS compounds, which tend to give false-positive results in biological assays due to non-specific or assay-interfering behaviors. Common examples include compounds that undergo redox cycling, bind covalently to proteins non-specifically, or aggregate in solution.
- Software tools that are used to flag PAINS and other reactive compounds during library design.
Intellectual Property (IP) Freedom
- To avoid legal challenges, the library contains compounds with clear intellectual property rights or molecules that are novel, and unpatented, allowing for future development without infringement risks.
Balanced Physicochemical Properties
- LogP: Efficient libraries of PROTAC contain compounds with a range of LogP values, ensuring the exploration of both hydrophobic and hydrophilic regions of chemical space.
- pKa: The range of acidic and basic properties should be covered to increase the likelihood of binding interactions across diverse biological environments.
PROTAC’s chemical libraries are unique as an efficient chemical library balances diversity, drug-likeness, synthetic accessibility, and biological relevance, which increases the chances of discovering active compounds that can be optimized into lead candidates.
What should you know about our
designed compound library?
- All fragments/linkers are non-toxic, non-tumorigenic, and commercially available.
- The size of the library ranged from 100 to 1000 compounds, depending on the availability of data for each library that met the required parameters.
- A separate service request should be sent for libraries larger than 1000 compounds.
- The offered fragment/linker libraries can be linked to a vast variety of lead compounds for structure development or molecular transformation.
- After the drug discovery pro receives the requested library's fees, the requestor should proceed to the service request to fill out the necessary information. The library CSV file is then delivered to the requestor via email in 7-14 business days.
- The libraries are updated once a month to ensure that they cover all of the lead diversity that may require equivalent diversity in the library fragments/linkers.
- All compound libraries are registered and can be purchased authentically at any time by contacting drug discovery pro.
“Fsp³” refers to the fraction of an atom’s bonds that are sp³ hybridized in a molecule. It’s a measure commonly used in chemistry, particularly in drug design and medicinal chemistry, to describe the three-dimensionality or “sp³ character” of a molecule.
- sp³ hybridization occurs when an atom (typically carbon) forms four single bonds, leading to a tetrahedral geometry.
- The Fsp³ value is calculated as:
A high Fsp³ value (closer to 1) indicates more sp³ hybridization, implying that the molecule is more three-dimensional (less flat). A low Fsp³ value (closer to 0) indicates more sp² hybridization, meaning the molecule is more planar.
In drug discovery, molecules with higher Fsp³ values are often associated with better solubility, lower lipophilicity, and improved bioavailability.
The LogS value refers to the logarithm of a compound’s solubility in water, usually expressed in mol/L. It’s commonly used in medicinal chemistry and drug discovery to predict how soluble a substance is in an aqueous environment. Since solubility is an important factor in the bioavailability of drugs, the LogS value helps estimate how well a drug might dissolve in the body, which can influence absorption.
- LogS is a logarithmic scale, so:
- A higher LogS value indicates better solubility.
- A lower LogS (more negative) suggests poor solubility.
For example:
- A LogS of 0 means the compound has a solubility of 1 mol/L.
- A LogS of -4 means the compound has a solubility of 10⁻⁴ mol/L, or 0.0001 mol/L, which is considered low solubility.
In drug design, compounds with very low LogS values might struggle to dissolve properly in the body, making them less effective as medications. Ideal drug candidates typically have moderate solubility, so they are absorbed well but not so soluble that they dissolve too quickly or cause formulation issues.
Covalent binders are molecules, often drugs, that form a covalent bond with their biological targets, typically proteins. This bond results in irreversible inhibition of the target, unlike non-covalent interactions, such as hydrogen bonds, ionic bonds, or Van der Waals forces, which are weaker and reversible. Covalent binding creates a lasting attachment to the target. This mechanism has significant applications in drug discovery, especially for targeting enzymes or receptors in diseases like cancer or bacterial infections.
Key Features of Covalent Binders:
- Irreversibility: Once a covalent bond forms between the binder and its target, it is typically irreversible. This means that either a new protein must be synthesized, or some cellular mechanism must be employed to remove the bound complex.
- High Potency: Because covalent inhibitors create irreversible, durable bonds, they often exhibit high potency. This strong bond allows using lower doses to achieve effective results.
- Selectivity: Covalent drugs are designed with a “warhead,” which is a reactive group that targets particular residues, often cysteine, lysine, or serine, in the active site of the target protein. This design provides a level of specificity in the binding process.
- Duration of Action: Due to the irreversible nature of the binding, covalent binders often have prolonged effects. This characteristic means that less frequent dosing is required.
Examples of Covalent Binders:
- Aspirin: Irreversibly inhibits the enzyme COX (cyclooxygenase), reducing inflammation.
- Clopidogrel (Plavix): Forms a covalent bond with a platelet receptor to prevent blood clotting.
- Ibrutinib: A covalent inhibitor of Bruton’s tyrosine kinase (BTK) used in certain cancers like chronic lymphocytic leukemia.
Advantages:
- Prolonged duration of effect due to irreversible binding.
- Potential to inhibit difficult-to-target proteins.
- High selectivity when designed appropriately.
Challenges:
- Potential off-target effects if the reactive warhead binds to unintended proteins.
- Risk of toxicity due to the irreversible nature of the binding.
Covalent drugs have become an exciting area of research, especially in oncology and immunology, where selective, long-lasting inhibition of protein targets can offer therapeutic benefits.
The LogP value is a measure of a compound’s lipophilicity, which indicates how well the compound can dissolve in fats or lipids compared to water. More specifically, it is the logarithm of the partition coefficient (P) of a substance between two phases: octanol (a lipid-like organic solvent) and water. The partition coefficient (P) is the ratio of the concentration of a compound in octanol to its concentration in water:
Key Points about LogP:
- High LogP value (positive): Indicates the compound is more lipophilic, meaning it dissolves better in fats or oils than in water. Lipophilic compounds can cross lipid-rich biological membranes more easily, such as the blood-brain barrier.
- Low LogP value (negative): Indicates the compound is more hydrophilic, meaning it dissolves better in water than in fats.
Significance of LogP:
- Drug Absorption and Permeability: Drugs with a moderate LogP (usually between 1-3) tend to have better permeability across cell membranes, as they balance both lipid and water solubility.
- Bioavailability: LogP values influence how well the body absorbs a drug. Too high of a LogP (typically >5) can result in poor solubility in aqueous environments like blood plasma, while too low of a LogP may prevent the drug from crossing lipid membranes.
- Pharmacokinetics: LogP can also influence the distribution, metabolism, and excretion of a drug. Highly lipophilic drugs may accumulate in fatty tissues, whereas hydrophilic drugs are often more easily excreted.
Ideal LogP Range for Drugs:
- LogP between 1 and 3 is often optimal for oral drugs because it provides a balance between solubility and permeability.
- Drugs with a LogP value greater than 5 may have poor water solubility and bioavailability.
- Drugs with a LogP value less than 0 may have trouble crossing cell membranes.
Examples:
- Caffeine: LogP ~ 0.2 (moderately hydrophilic, good balance for CNS penetration).
- Ibuprofen: LogP ~ 3.5 (lipophilic, easily crosses cell membranes).
- Vitamin C: LogP ~ -1.85 (highly hydrophilic, water-soluble).
Understanding LogP is crucial in drug design to optimize a compound’s pharmacokinetic properties.
Brain penetrants refer to drugs or compounds that can cross the blood-brain barrier (BBB) and reach the central nervous system (CNS), where they can exert their effects. The blood-brain barrier is a highly selective and protective barrier that prevents many substances, especially large or polar molecules, from entering the brain. This presents a challenge for drug development, particularly for neurological diseases like Alzheimer’s, Parkinson’s, epilepsy, and brain cancers, where the drug must reach brain tissue to be effective.
Key Characteristics of Brain Penetrants:
- Lipophilicity: Compounds that are more lipophilic (fat-soluble) tend to penetrate the BBB more easily because the barrier is made up of tightly packed endothelial cells with lipid-rich membranes.
- Small Size: Smaller molecules (typically < 500 Da) are more likely to cross the BBB.
- Low Polar Surface Area (PSA): A low polar surface area (usually < 90 Ų) is another important factor, as it influences how easily the compound can traverse the lipophilic environment of the BBB.
- P-glycoprotein Substrate: Some compounds that can cross the BBB are actively pumped back out by P-glycoprotein (P-gp), an efflux transporter. To be effective, brain-penetrant drugs often need to avoid being substrates for P-gp to prevent rapid clearance from the CNS.
- Other Mechanisms: In some cases, drugs can use carrier-mediated transport, receptor-mediated transcytosis, or other specialized pathways to cross the BBB.
Challenges in Developing Brain Penetrants:
- Safety and Selectivity: The brain is sensitive, so drugs that cross the BBB must be highly selective to avoid unwanted side effects.
- Efflux Transporters: As mentioned, efflux pumps like P-glycoprotein and others (e.g., breast cancer resistance protein, BCRP) can limit the effectiveness of drugs by actively transporting them out of the brain.
- Metabolic Stability: Brain-penetrant drugs need to remain stable and effective within the brain’s environment without being rapidly degraded.
Examples of Brain-Penetrant Drugs:
- Levodopa (L-DOPA): Used to treat Parkinson’s disease, it crosses the BBB where it’s converted into dopamine.
- Diazepam (Valium): A benzodiazepine used for anxiety and seizure control that readily crosses the BBB due to its lipophilicity.
- Donepezil (Aricept): Used to treat Alzheimer’s disease by inhibiting acetylcholinesterase in the brain.
Brain-Penetrant Drug Design:
Pharmaceutical researchers focus on designing drugs that are effective at targeting CNS conditions and able to cross the BBB efficiently. Prodrug approaches (where a compound is metabolized into the active drug once inside the brain) or drug delivery systems like nanoparticles are also explored to improve brain penetration.