Searching Substances by Structure
- When you click on the Draw button next to any search window, the SciFinder-n structure drawing tool will open. See below:
- Note the drop-down menu at top. SciFinder-n offers two built-in structure editors: CAS Draw and ChemDoodle. This lecture will focus on CAS Draw. You can also use external structure drawing programs, such as ChemDraw which can export a structure as a MOL file. See Import below. ChemDraw Professional integrates directly with SciFinder-n for easy transfer of structure information.
- Top horizontal row of icons
- New - start drawing a new structure
- Import - Enter the name of a saved CXF or MOL file that you wish to modify or search in SciFinder-n.
- Export - Once you have crated a structure, you can export it as a CXF or MOL file.
- Save as Template - You can save the structure in the current structure drawing window as a template to reuse as a starting point for structure building and searching.
- Center Structure - Moves the structure you have drawn to the center of the drawing field
- Preferences - Lets you set bond lengths and angles as you prefer. This only affects the way structures display; it has no effect on searching.
- Keyboard shortcuts - Opens a list of single-keystroke shortcuts that can save time for the experienced user.
- Text template window - You may enter a CAS Registry Number, SMILES string or InChI, then click Enter, and the identified structure will appear in the structure drawing field or you to modify or search.
- Search window to import structures from CAS Registry Numbers, SMILES strings or InChI Keys
- Furthest-left bertical tool bar Note that when you clickon one of these icons, a description of its function appears in the main drawing window.
- Lasso - Select objects by clicking on them, or clicking and dragging a line around them.
- Pencil - Draw or change atoms or bonds
- Atoms - Opens a periodic table from which you may select any atom to draw with the Pencil tool. Selected atoms show up in the window just below the drawing field. When you hover your cursor over an element in the table, it will display the atomic number, element name (in English), atomic weight, and the column and row names to which it belongs, see below. Use the close button when you are done selecting atoms. Note, too, that deuterium and tritium are available at the bottom of the table.
- Variables - List of available variables: See below.
- Select fragment attachment - Assign an attacment point or points to a fragment for use in R-groups (se below).
- Add positive charge - Lets you add one or more positive charges to a structure you'v drawn. This does not affect searching.
- Repeating Groups - If you wish to specify a repeating group in your structure, dfaw it, then shoose this tool and draw a selection box around the group. A window will appear in the horizontal bar above the drawing window where you can specify a range of how many repeats, from 0 to 20.
- Variable attachment points - Used to allow variation in where a given subsituent may be attached to a ring system. Create the ring system structure, then creae the substituent separate from the ring(s). Now click on the Variable Attachment tool, then on the substituent, then on each atom on the ring system where you wish to allow th substituent to be attached. Note that this does not mean that multiple copies of the substituent will necessarily be attached. The substituent will be shown as connected by dotted lines to the selected ring atoms.See example below.
- Map atoms - Designate corresponding atoms in reactants and products
- Bonds formed/broken - Clickon a bond in a reactant or product to indicate that the bond is broken or formed in the reaction.
- Marquee - Lets you draw a rectangular box to select an atom or group of atoms (e.g. for deletion). Click in the upper-left hand corner of the area you wish to select, then hold and drag to the lower right-hand corner. Release the button to select.
- Lock Ring - This tool is used for substructure searching. Select it, then click on an atom in the desired ring to prevent answers in which there is a ring fused onto the drawn structure.
- Rotate fragment - This tool lets you click on an atom in your structure and then use your mouse to rotate the structure around that atome (in a 2D sense). Note that rotating the structure does not affect searching, only display.
- Reaction Arrow - Only used for reaction searching. This will be discussed in Lecture 15
- Map Atoms - Only used for reaction searching. This will be discussed in Lecture 15/
Second left-hand vertical tool bar:
- Rectangle selection tool - Click ion the upper left hand corner of the area you wish to enclose and select, then drang to the lower right hand cordner and release, to select all the atoms and bonds within the rectangle.
- Eraser -Delete atoms and bonds
- Shortcuts - Opens a table of "shortcut" symbols for commonly used functional groups, such as Me, Et, NO2, etc. Note that if you use ashortcut group in drawing your structure in a substructure search, no further substituion is allowed on the shortcut group. Note that a few shortcuts appear in two different forms. This makes no difference in searching, but can be used to get a better appearance in the structure diagram.
- R-groups - These are "build your own" variable groups. You may create up to 20 different R-groups per structure (R1, R2, R3 etc.) selecting from Atoms, Variables and Shortcuts. Note that the option to nclude structure fragments in the R-group is greyed out as no structure fragments have been designated yet. See below for more infomration.
- Structure Templates - These are a set of pre-defined structures which you can use as starting points for structure drawing. See the full list of structure types below, and an example of one of the types in full. Note that you can create you own user-defined templates using the Save as Template tool mentioned above. Note, too, that you can seaerch all the templates by name to find a particular one. See the opening table, and the expanded Alkaloids example.
- Add negative charge - See "Add positive harge" above.
- Chain - Click and drag this tool to create a chain of single-bonded carbon atoms.
- Substance role in reactions - Click on an atom and designate whether the structure fragment it is in is a reactant, product or other
- Lock rings - Clicking on this icon displays a menu of several tools: Click on an atom in a ring to designate that no additional ring fusion on tht ring is allowed.. Lock atoms forbids non-hydrogen substitution on te atom; Rotate fragment and Flip fragment. These last two only affect the appearance of the display, and do not influence searching.
- Add reaction arrow - Click and drag to create a reaction arrow, with reactants to its left, and products to its right.
Bertical tool bars on the righthand side of the drawing window:
- These provide access to commonly used atoms and bond types. Note that some boxies have an arrow in the lower right-hand corner. These indicate that more choices appear when you click on the box.
- C = Carbon; H = Hydogen (Click on the arrow for Deuterium and Tritium)
- O = Oxygen; S= Sulfur
- N = Nitrogen; P = Phosphorus
- Cl = Chlorine (click on arrow for Fluorine, Bromine, Iodine); Si = Silicon
- Single bod; Double bond (Click on arrow for Triple bond and Unspecified bond.)
- Stereo bond up (Click on arrow for Stereo bond down, Stereo double bond up, Stereo double bond down); Cis=trans double bond.
- Cyclopentane ring; Cyclopentadiene ring
- Cyclohexane ring; Benzene ring
- Cycloheptane ring; 3-15 soded romg
Multiple Points of Attachment
This tool allows you to specify that a given atom/group may be attached at multiple possible points on a ring structe. To do so, draw the ring structure, then draw the desired atom/group as an unattached fragment, and clig on the Multiple Points of Attachment tool, then click on the fragment, and draw lines to the desired ring atoms. Below is an example using a Cl atom and a naphthalene ring.
Note how the resulting structure shows a solid line from the Cl tothe center of one of the naphthalene rings, with dotted lines going to the selected ring atoms.
Structure Fragments in R-Groups
To create an R-group including structure frangments, first draw each individual frgment you wish to create. In the example below, I created an amide group, a triphenylsilyl group and a alkyl, sulfonyl group. Then, click the Fn tool, and click on the point of attachment you desire on each fragment. Note that if you want to use a fragment as a bridging group, you can create multiple points of attachment on the same fragment.
Note how each attachment point is labeled, and the fragment as a whole hs an F-number assigned.
Then, click on the R tool, choose an unused R number, and select the atoms, variables shortcuts or fragments you wish to include in the R group. Fragments will appear in a table at the bottom of the R-group window. In this case, R1 includes fluorine, trifluoromethyl, and the three structure fragments I drew. I could now close the window and attach R1s wherever I want in my desired molecular structure for searching.
With the tools above, drawing structures in SciFinder-n is relatively straightforward. SciFinder automatically checks for "normalized" bonds in aromatic structures or tautomers.
Some general tips -- While you can do most functions in any order, I prefer to do the following:
- Plan out your structure before you start drawing. Think about whether you are doing an exact structure search or substructure search. Are there templates you can use? Think ahead as to what groups can be represented by shortcuts. Note that SciFinder (and the underlying database) do not allow substituents to be attached to most shortcuts.
- Is there a known substance that you can use as a starting point, rather than drawing from scratch? If so, look up the substance in SciFinder-n and click on its structure diagram, then select "Edit Structure". Alternatively, if you can find its CAS Registry Number , SMILES string or InChi number, you can enter it in the CAS Draw search window and pull it up that way.
- Whe starting from scratch"
- Draw any ring structures in the compound first.
- Then draw/attach chains as needed.
- Then change any atoms into heteroatoms, variables, shortcuts, R-groups as necessary.
- Then modify bonds as needed. This is where you can add stereochemistry if desired.
- Then consider any added restrictions: locking down substitution at some sites or locking out ring fusion.
- Previewing substructure searches is a good idea to make sure you're getting the kind of results you anticipated.
Structure Drawing Example: Feropolone
As an example, let's take a look step-by-step at the drawing of the structure of feropolone (Note: the screenshots below were made with the CASDraw editor, but the procedure is essentially the same ith the ChemDoodle editor.
First, use the ring drawing tools to draw in the ring portions of the structure -- the benzene ring tool for the benzene ring on the right, then the cyclohexane ring tool for the ring on the left. To attach the six-membered ring to the benzene ring on the right, place the cursor over the upper-right bond in the benzene ring. It should be highlighted in red. Then click, and a cyclohexane ring will be fused onto the benzene ring, as below:
Now, draw the chain connecting the two rings. Select the pencil t or chain tool, draw a six-membered chain, then use the pencil to bond to the ring.
Continuing with the pencil tool, now draw in the other side chains on the rings and bridging chain. Don't worry about the fact that the atoms are carbon and the chains are all single bonds. We'll fix that part in a moment.
Now, we can use the Atom button, or the menu of atoms at the bottom of the screen with the pencil tool to change all the simple carbon atoms into oxygens where needed. Click on the "O" button at the bottom of the screen. Note how the window to the left of the buttons now shows an O. That is the current atom that will appear when you draw. Now, move the pencil too cursor over each atom in turn and click once to change it into an oxygen. Note that you don't have to draw in hydrogens; the system assumes that hydrogens will fill any unused bonds in your structure unless you specify otherwise.
Now, use the Shortcut tool to add methyl (Me) and hydroxyl (OH) groups where needed. Notice that whenever your cursor hovers over a shortcut group, either in the table of shortcuts or in the drawing window, CAS Draw shows you what the fully drawn out shortcut would look like.
Finally, there are some single bonds that need to be changed to double bonds: the two ring C-O bonds and the cyclohexane C-C bond on the right of the right-most ring. To do that, change the atom back to C (click on the C button), then click on the double bond button in the row below it. Now move the pencil cursor to the appropriate bonds, make sure the bond is highlighted, then click to make the single bond a double bond.
Always check over your structure before clicking OK. If you made a mistake and forgot to check it, you can always come back and fix it, but it saves time to check it over first.
When you click OK after creating a structure, you get back a substance answer set. The initial answer set display for feropolone is shown below:
Note that the display above is basically the same as for the aspirin etc. answer set EXCEPT for the indication of "as drawn", substructure and similarity answer sets.
Here's another example. The structure drawn is that of dibenzothiophene. After clicking OK we cp,e tp tjos screem/
- Note that the drawn structure appears in a small box under the Search button. In the box are buttons for Edit Structure (which returns you to the structure drawing tool with the boxed structure inside) and Remove which deletes the structure from the search windoww.
- Below that, is a button, Search Patent Markush. We will return to this item further below.
- If you click on the Search (magnifying glass) icon, you come to here:
- Above is the "as drawn" answer set for dibenzothiophene. Note that in this Relevance sort, the starting structure is listed first.
- The Substance Class filter has been expanded. Note that the results of the "as drawn" set include: Salt and Comound with (that is, mixtures), Polymer and Coordination Compound. All of these have the unsubstituted strcture as part of their Registry recrd, so they appear in the answer st.
- Note, too: The filters for Stereochemistry and Isotopes appear. Each sterochemical variation on the parent structure and each isotopically-labelled substance gets its own Registry Number, but is considered structurally identical to the prent compound.
- Below is a portion if the Substructure answer set:. It has been sorted by CAS RN in descending order so that you can see some of th ekinds of substitution on the basic structure we searched. There can be other atoms, or more complex structures attached anywhere on the molecule, including additional rings fused onto the ring structure.
- Below is a portion of the Similarity answer set. Similarity searches use an algorithm to measure the similarity in shape of molecules. The drawn molecule is a 100% match for itself. Similar molecules may have other changes besides attachments to the substructure. For example, one of the sic-membered rings in the starting structure might have five members in the lower ranges of similarity.
- Note that you can filter by the degree of similarity. The portion of the answer set shown has been filtered to the 70-74% range. In the lower part of the display, you can see an example with a cyclobutadiene ring replacing one of the benzene rings, and another with a sulfur atom replacing a carbon in one of the benzene rings, as well as some with more confentional attachments.
- Similarity searches are frequently used in drug discovery research. For example, you can take a drug of known activity and do a similarity search, then refine to eliminate commercially available substances (including drugs already on the market), then refine by, for example, Reference Role: Biological Study or by a particular Bioactivity Indicator or Target Indicator to locate promsing drug candidates.
Patent Markush Searching
In SciFinder-n, Markush structure searching is separate from the "as drawn"/substructure/similarity searching. In part, this is because the markush search does not retrieve specific substances. Rather it retrieves Markush structures (see Lecture 7) and the patents with which they are associated. Below is a portion of the answer set for a Markush search of dibenzothiophene.
- Note that both "As drawn" and Substructure answer sets are available.
- Next to the Patent Markush header is the total number of answers in the displayed answer set. To the far right is the Sort drop-down menu. The Default sort is by Relevance; you can also sort by Patent Number (ascending or descending).
- Next down is a tab for retriebing selected or all References for the patent documents listed. To the right are Download, E-Mail and Save and Alerts icons.
- On the left, beneath the "As drawn" and "Substructure" links are the Filter options. The ONLY filter option for the Patent Markush answer sets.are the issuing Patent Office. and the CA Section. However, if you retrieve the Reference records for the patents, you can manipulate them just as you would any other Reference answer set.
- Brief records: Contain the source Patent Number, the Markush structure which was retrieved, the Title, the brief Abstract, which Claim the structure appears in, links to PatentPak and other full text sources, and any notes associated with the structure. If you click on the Patent Number, it takes you to the Reference Detail for that patent.
- Note: If you are trying to find all patents for a given substance or set of substances, it is important to do BOTH a conventional substance search AND a Markush search. A patent covering your substance of interest may have claimed the substance either specifically, or as part of a Markush claim, and either could be prior art for your purposes.
Chemscape Analysis is a new feature in SciFinder-n; a visualization tool that can be applied to any Substance answer set created by a structure search. To use it, click the Create Chemscape Analysis button as seen in any of the answer set examples above. A new tab will open with the Chemscape results.
Chemscape visualizes the similarity and patent landscape for a set of substance results. The location of the substance bar in the visualization corresponds to the similarity of the substance to the query and the height of the substance in the visualization corresponds to the number of patents in which the sequence has been published.
Below is an example of the opening Chemscape display for the substructure search sown above, filtered to commerically available substances only.
Above is the initial display of the Chemscape analysis of the answer set., which opens in a new tab.
Icons on the upperleft:
My Chemscape - Displays a list of saved Chemscapes
Substance - Displays the box shon in the image, with the following options
Structural Similarity - Lets you select the range of strucutre similarity displayed.
Molecular Weight - Lets you select the range of molecular weights displayed.
Current Assignee - Lets you display substances by the assigne of patents in which they appear Click on the Add button next to a group sto see a list of assignees. Select from them to create the Group yoou've chosen.
CPC - Lets you create Groups using the CPC classifications codes. Click on Add to see a list of CPC codes from the patents in which the compounds appear.
IPC - Same as above, but using the IPC (International Patent Classification Code) codes.
Publication Year - Create Groups by publication year of the patents
Jurisdiction - Create Groups by theissuing patent office/country (e.g. US, China, WIPO)
Filters - Lets you filter the results by a patent count, range of patent counts, or limit to substances with no patent filed.
Add structure - Lets you add new structures to your current Chemscape and map their positions.You can search for structures to add by name or by structure drawing.
Search - Lets you search for specific patents by keyword (title, abstract, description and/or claims) legal status, publication date and/or current assignee. You may also do a structure search within the answer set.
Toggle control panel - Opens and closes the current control panel
Bottom right controls - Let you adjust your screen view: move left or right, expand/contract the image, or take a screen shot.
Click and drag on an empty portion of the display to rotate the 3-D viewing angle.
Click on a substance "tower" to see the CAS Registry Number, structure diagram, patent count, names/synonyms, molecular weight of the substance. You can mark the substance for later reference. If you click on the CAS Registry Number, a new tab will open with the Substance Detail record for the substance, from which you can then view properties, retrieves References or Reactions, and do all the other functions you can do from a Substance record in SciFinder-n.
Select Structure - Click on this button, then you can click and drag to create a rectangular selection box for viewing that region of the Chemscape, or saving as a new Chemscape.
Save - Lets you cave the current Chemscape, assign a name and (optionally) a description for future reference. This creates a saved Substance search in your Search History. . Click Rerun Search to be able to see the saved Chemscape.
You can save substance (or Markush) searches and create search alerts. Whenever a new substance appears matching your query, you will be notified. Alternatively, you can take the results of a substance search, retrieve the References associated with them and creaate a Reference search alert. In that case, whenever a new Reference containing one of the substances in your original answer set appears, you will be notified. There is currently no way in SciFinder-n to create an alert that finds new substances and automatically retrieves the references that they appear in (though there is sucha function in STN). You have to create the Substance search alert, then, when you receive a notification, get the References fmanually, then look at the resulting References.
. © 2023 Charles F. Huber
This work by Charles F. Huber is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
Based on a work at guides.library.ucsb.edu
SciFinder-n screenshots are copyright © 2023 by American Chemical Society and are used under fair use for educational purposes only.