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opthitlead [2013/10/09 08:31] – created rkissopthitlead [2024/04/09 08:37] (current) – rkiss
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 ====== Optimize hits and leads ====== ====== Optimize hits and leads ======
  
-[[http://youtu.be/Kb7HIPNpHzw|{{:hello.png?100|}}]] **[[http://youtu.be/Kb7HIPNpHzw|Check out how Ed, the chemist optimizes his identified hit using Mcule >>]]**+[[http://youtu.be/Kb7HIPNpHzw|{{:hello.png?100|}}]] **[[http://youtu.be/Kb7HIPNpHzw|Check out how Ed, the chemist optimizes his identified hit using Mcule »]]**
  
 Mcule offers a continuously growing set of intuitive, easy-to-use modeling applications specifically designed to evaluate and generate ideas in the hit/lead optimization process. Mcule offers a continuously growing set of intuitive, easy-to-use modeling applications specifically designed to evaluate and generate ideas in the hit/lead optimization process.
  
-**__[[usecases|Go back to use cases >>]]__**+**__[[usecase1cd|Optimize binding affinity and selectivity with 1-Click Docking »]]__**
  
-== A) Optimize binding affinity and selectivity with 1-Click Docking ==+**__[[usecasepropcalc|Property calculator »]]__**
  
-Molecular docking simulations predict the binding orientation and affinity of a ligand to a target.+**__[[usecasetoxcheck|Toxicity checker »]]__**
  
-1. Go to **[[http://mcule.com/apps/1-click-docking|LEAD OPTIMIZATION / 1-CLICK DOCKING]]**+--
  
-2. Specify your existing hit/lead (either by drawing or by providing a chemical identifier such as mcule ID, SMILES, InChI or InChIKey) +**__[[usecases|Go back to use cases »]]__**
- +
-3. Select or upload a target +
- +
-4. Click on **"DOCK"** +
- +
-5. After the docking calculation finishes you can check the estimated binding affinity (docking score - more negative means higher affinity) and visualize the critical interactions that have been formed between your ligand and the target by clicking on **"VISUALIZE POSE"**.  +
- +
-6. Go back and draw a slightly modified version of your hit/lead +
- +
-7. Click on **"DOCK"** +
- +
-8. After the docking calculation finishes you can compare the docking scores and the formed interactions of the modified molecule and those of the original hit/lead. +
- +
-9. To get an idea where the compound can be further adjusted, take a closer look at the binding mode (**"VISUALIZE POSE"**). Turn on the **"proteinsurface"** feature to see where is additional space for optimization. Red colored surface parts indicate polar regions. +
- +
-10. Continue testing new ideas and improve the docking scores. You can also run other Lead Optimization tools, such as **[[http://mcule.com/apps/property-calculator|Property Calculator]]** and **[[http://mcule.com/apps/toxicity-checker|Toxicity Checker]]** to make sure other properties of the ligand are not impaired. In fact, try to improve multiple things simultaneously by checking all properties of the same idea. +
- +
-11. You can check your previous 1-Click Docking results and queries **[[http://mcule.com/apps/1-click-docking/history|HERE]]**. If you run out of storage, check the **[[http://mcule.com/pricing|Price Plans]]** to upgrade. +
- +
-12. Additionally, you can take a step forward and calculate the binding affinity to off-targets, you don't want your ligand to bind to. For example to design a subtype specific inhibitor, you might need high binding affinity to subtype "A", but low affinity to subtype "B". For this select other targets and dock your ligand again. +
- +
-**__[[usecases|Go back to use cases >>]]__** +
- +
-== B) Generate new ideas and eliminate problematic parts by 1-Click Scaffold Hop == +
- +
-Scaffold hopping is about finding novel active ligands structurally different from a reference ligand (query). Scaffold hopping can be particularly useful during lead optimization to generate new ideas or to eliminate particular parts of your hit/lead to fix IP, toxicity, selectivity or pharmacokinetic issues. 1-Click Scaffold Hop is searching different subsets of **[[purchasable|Purchasable compounds]]**  +
-that might be structurally different but share pharmacophore properties with those of the query. +
- +
-1. Go to **[[http://mcule.com/apps/1-click-scaffold-hop|LEAD OPTIMIZATION / 1-CLICK SCAFFOLD HOP]]** +
- +
-2. Depending on your **[[http://mcule.com/pricing|Price plan]]**, you can choose from input collections with different sizes +
- +
-3. Specify your existing hit / lead / reference ligand (either by drawing or by providing a chemical identifier such as mcule ID, SMILES, InChI or InChIKey) +
- +
-4. Click on **"SCAFFOLD HOP"** +
- +
-5. After the calculation finishes you can find a number of diverse scaffolds that have similar pharmacophore properties as your query +
- +
-6. Click on **"VISUALIZE SIMILARITY"** to understand why the two compounds are similar. Corresponding parts are marked with different colors. +
- +
-7. Remember that all displayed hits are purchasable. To order any of them, click on the orange **"QUOTE"** buttons. +
- +
-8. You can check your previous 1-Click Scaffold Hop results and queries **[[http://mcule.com/apps/1-click-scaffold-hop/history|HERE]]**. If you run out of storage, check the **[[http://mcule.com/pricing|Price Plans]]** to upgrade. +
- +
-9. You can use the other Lead Optimization tools, such as **[[http://mcule.com/apps/1-click-docking|1-Click Docking]]**, **[[http://mcule.com/apps/property-calculator|Property Calculator]]** and **[[http://mcule.com/apps/toxicity-checker|Toxicity Checker]]** to further characterize the newly identified scaffolds +
- +
-**__[[usecases|Go back to use cases >>]]__** +
- +
-== C) Property calculator == +
- +
-ADMET properties heavily depend on physicochemical properties. For example, high logP (> 5) and molecular weight (> 500 g/mol) are typically associated with unsuitable ADMET profile. Property calculator creates a physicochemical property profile for your compound in seconds. You can reject compounds with unsuitable logP, insufficient number of H-bond acceptors/donors, too many rotatable bonds, etc. +
- +
-1. Go to **[[http://mcule.com/apps/property-calculator|LEAD OPTIMIZATION / PROPERTY CALCULATOR]]** +
- +
-2. Specify your existing hit/lead (either by drawing or by providing a chemical identifier such as mcule ID, SMILES, InChI or InChIKey) +
- +
-3. Click on **"CALCULATE"** +
- +
-4. Check the calculated properties of your original hit/lead. Depending on your **[[http://mcule.com/pricing|Price Plan]]**, you might see **Basic** as well as **Advanced** properties. Notice if there are properties in unsuitable/unacceptable ranges (e.g. too high logP). +
- +
-5. Go back and draw a slightly modified version of your hit/lead +
- +
-6. Click on **"CALCULATE"** +
- +
-7. After the calculation finishes you can check the individual properties and see if problematic properties got improved due to your modification in the hit/lead structure +
- +
-8. You can use the other Lead Optimization tools, such as **[[http://mcule.com/apps/1-click-docking|1-Click Docking]]** and **[[http://mcule.com/apps/toxicity-checker|Toxicity Checker]]** to make sure other properties of the ligand are not impaired. In fact, try to improve multiple things simultaneously by checking all properties of the same idea. +
- +
-**__[[usecases|Go back to use cases >>]]__** +
- +
-== D) Toxicity checker == +
- +
-Certain structural elements of a molecule can be responsible for toxicity. In fact, some substructural motifs occur more frequently in toxic compounds than in non-toxic ones. It therefore makes sense to eliminate such structural motifs from hits/leads as early as possible. Toxicity Checker is based on more than 100 toxic and promiscuous scaffolds. It displays an alert, when such a motif is found, and it displays the incriminated part of the molecule. +
- +
-1. Go to **[[http://mcule.com/apps/toxicity-checker|LEAD OPTIMIZATION / TOXICITY CHECKER]]** +
- +
-2. Specify your existing hit/lead (either by drawing or by providing a chemical identifier such as mcule ID, SMILES, InChI or InChIKey) +
- +
-3. Click on **"CHECK"** +
- +
-4. If the compound contains any potential toxic substructure, **"FAIL"** message will be displayed along with your structure and the problematic motif in red +
- +
-5. Go back and try to modify the problematic motif of your hit/lead +
- +
-6. Click on **"CHECK"** +
- +
-7. Continue the modifications, until no alert is displayed +
- +
-8. You can use the other Lead Optimization tools, such as **[[http://mcule.com/apps/1-click-docking|1-Click Docking]]** and **[[http://mcule.com/apps/property-calculator|Property Calculator]]** to make sure other properties of the ligand are not impaired. In fact, try to improve multiple things simultaneously by checking all properties of the same idea. +
- +
-**__[[usecases|Go back to use cases >>]]__**+
  
opthitlead.1381307487.txt.gz · Last modified: 2013/10/09 08:31 by rkiss