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Table of Contents
Optimize hits and leads
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.
Optimize binding affinity and selectivity with 1-Click Docking >>
Generate new ideas and eliminate problematic parts by 1-Click Scaffold Hop >>
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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 compounds that might be structurally different but share pharmacophore properties with those of the query.
1. Go to LEAD OPTIMIZATION / 1-CLICK SCAFFOLD HOP
2. Depending on your 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 HERE. If you run out of storage, check the Price Plans to upgrade.
9. You can use the other Lead Optimization tools, such as 1-Click Docking, Property Calculator and Toxicity Checker to further characterize the newly identified scaffolds
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 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 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 1-Click Docking and 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.
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 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 1-Click Docking and 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.