opthitlead
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opthitlead [2013/10/09 08:35] – rkiss | opthitlead [2014/01/01 15:51] – flack | ||
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====== Optimize hits and leads ====== | ====== Optimize hits and leads ====== | ||
- | [[http:// | + | [[http:// |
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. | ||
- | **__[[usecase1cd|Optimize binding affinity and selectivity with 1-Click Docking | + | **__[[usecase1cd|Optimize binding affinity and selectivity with 1-Click Docking |
- | **__[[usecase1csh|Generate new ideas and eliminate problematic parts by 1-Click Scaffold Hop >>]]__** | + | **__[[usecase1csh|Generate new ideas and eliminate problematic parts by 1-Click Scaffold Hop »]]__** |
- | **__[[usecasepropcalc|Property calculator | + | **__[[usecasepropcalc|Property calculator |
- | **__[[usecasetoxcheck|Toxicity checker | + | **__[[usecasetoxcheck|Toxicity checker |
-- | -- | ||
- | **__[[usecases|Go back to use cases >>]]__** | + | **__[[usecases|Go back to use cases »]]__** |
- | ====== Optimize binding affinity and selectivity with 1-Click Docking ====== | ||
- | |||
- | Molecular docking simulations predict the binding orientation and affinity of a ligand to a target. | ||
- | |||
- | 1. Go to **[[http:// | ||
- | |||
- | 2. Specify your existing hit/lead (either by drawing or by providing a chemical identifier such as mcule ID, SMILES, InChI or InChIKey) | ||
- | |||
- | 3. Select or upload a target | ||
- | |||
- | 4. Click on **" | ||
- | |||
- | 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 **" | ||
- | |||
- | 6. Go back and draw a slightly modified version of your hit/lead | ||
- | |||
- | 7. Click on **" | ||
- | |||
- | 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. | ||
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- | 9. To get an idea where the compound can be further adjusted, take a closer look at the binding mode (**" | ||
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- | 10. Continue testing new ideas and improve the docking scores. You can also run other Lead Optimization tools, such as **[[http:// | ||
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- | 11. You can check your previous 1-Click Docking results and queries **[[http:// | ||
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- | 12. Additionally, | ||
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- | **__[[usecases|Go back to use cases >> | ||
- | |||
- | ====== 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:// | ||
- | |||
- | 2. Depending on your **[[http:// | ||
- | |||
- | 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 **" | ||
- | |||
- | 5. After the calculation finishes you can find a number of diverse scaffolds that have similar pharmacophore properties as your query | ||
- | |||
- | 6. Click on **" | ||
- | |||
- | 7. Remember that all displayed hits are purchasable. To order any of them, click on the orange **" | ||
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- | 8. You can check your previous 1-Click Scaffold Hop results and queries **[[http:// | ||
- | |||
- | 9. You can use the other Lead Optimization tools, such as **[[http:// | ||
- | |||
- | **__[[usecases|Go back to use cases >> | ||
- | |||
- | ====== 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/ | ||
- | |||
- | 1. Go to **[[http:// | ||
- | |||
- | 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 **" | ||
- | |||
- | 4. Check the calculated properties of your original hit/lead. Depending on your **[[http:// | ||
- | |||
- | 5. Go back and draw a slightly modified version of your hit/lead | ||
- | |||
- | 6. Click on **" | ||
- | |||
- | 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:// | ||
- | |||
- | **__[[usecases|Go back to use cases >> | ||
- | |||
- | ====== 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:// | ||
- | |||
- | 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 **" | ||
- | |||
- | 4. If the compound contains any potential toxic substructure, | ||
- | |||
- | 5. Go back and try to modify the problematic motif of your hit/lead | ||
- | |||
- | 6. Click on **" | ||
- | |||
- | 7. Continue the modifications, | ||
- | |||
- | 8. You can use the other Lead Optimization tools, such as **[[http:// | ||
- | |||
- | **__[[usecases|Go back to use cases >> |
opthitlead.txt · Last modified: 2024/04/09 08:37 by rkiss