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Typical use cases of Mcule

Download a subset of the Mcule database

1. You can create custom subsets of the Mcule database by running searches in FIND CHEMICALS, or executing workflows under HIT IDENTIFICATION

2. All your search results (outputs of searches in FIND CHEMICALS, or workflows in HIT IDENTIFICATION) can be found under COLLECTIONS

3. You can select any of your collections, and click on the “EXPORT” button in the top right corner to download it in SDF, SMILES, InChI, InChIKey, mcule ID formats

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Extend your in-house compound deck

The Mcule database contains millions of Purchasable compounds providing a great pool of compounds to extend your existing in-house library. You can prefilter the Mcule database based on your own criteria, export it, select the interesting compounds in-house and come back to us with a list of mcule IDs to order. We can also help and assist you if you have any special criteria or requests. For example, you can provide us with your in-house library under a Non-Disclosure Agreement, and we can do the compounds selection based on your criteria. Please contact us (info@mcule.com) if you would like to discuss this in more detail.

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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.

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A) 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 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)

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 Property Calculator 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.

11. You can check your previous 1-Click Docking results and queries HERE. If you run out of storage, check the 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.

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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 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

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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 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.

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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 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.

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Hit identification

Check out how Ed, the chemist identifies new chemical starting points for his project using Mcule >>

You can identify new inhibitors/modulators of your target (receptor, enzyme, nucleid acid, etc.) by searching the Mcule database. In Mcule, you can easily build virtual screening workflows by putting together molecular modeling tools like LEGO bricks. Virtual screening workflows are a set of filters and calculations. Filters can eliminate compounds that unlikely binds your target or have other unwanted properties and calculations can rank order the best candidates for example by their estimated binding affinity. You can filter the whole mcule database (over 5 million compounds) with several tools until you select the most promising compounds (10-1000). Additionally, you can order the best hits by just a few clicks.

A) Structure-based virtual screen

Structure-based virtual screening utilizes the 3D structure of the target when searching for new hits. During the screening, predicted 3D structures of small molecules are fitted into the binding site of the experimentally determined or modeled 3D structure of the target (docking calculation). The 3D structures of thousands of large macromolecules have been already determined by X-ray crystallography or NMR spectroscopy and can be easily selected or uploaded in Mcule. Small molecules predicted to form critical interactions with the target get better (more negative) docking scores and are ranked higher.

1. Go to HIT IDENTIFICATION / STRUCTURE-BASED VIRTUAL SCREEN

2. Select the input collection if other than all Purchasable compounds of the Mcule database

3. The loaded template workflow includes a number of individual workflow steps that will be executed sequentially on the input collection. Detailed description of the available workflow steps can be found HERE.

4. RUN

go back and change pm-s and see the results output collection size sampler

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B) Ligand-based virtual screen

Ligand-based virtual screening does not utilize the 3D structure of the target when searching for new hits. Instead, it is based on the structure of a reference ligand (endogenous ligand, known inhibitor, etc.) that binds to a target and/or exhibits some beneficial effect. In ligand-based virtual screening, compounds are typically ranked based on the similarity to the reference ligand (query).

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usecases.1381307293.txt.gz · Last modified: 2013/10/09 10:28 by rkiss