[ 2D Bioisostere | 3D Bioisostere ]

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In drug design bioisosteres can be used to reduce toxicity, change bioavailability, alter metabolism and change activity of lead compound. Bioisosteres are chemical substituents with similar chemical or physical properties which produce broadly similar biological properties to another chemical compound.

7.9.1 2D Bioisostere

To find 2D Bioisosteres:

Step 1: Read in a chemical into a chemical table. Right click Chemistry/Find Bioisosteres for a Group.

Step 2: Download Database If you do not see this link it means you already have the database in your ICM directory. If yo do not have it - download bioisostere group database groupsubst.molt and save it into your ICM directory. There is a link at the bottom of the dialog window which will direct you to the correct place to download.

Step 3: Setup the Search Select the tab for 2D Database at the top of the dialog window. Left click and drag over the group you wish to find a bioisostere for. Select if you want to "Match Scaffold Attachment". It matches the attachment atom from the R-group which you're trying to substitute with the the database. In this example the attachment is C^3 (SP3 Hybridized), so if you select this option it will only return hits where scaffold attachment column contains C^3. Select if you want to generate Full Scaffold or just show the R-group. Click OK to run the search.

Step 4: Results Table In this example we find tetrazole which is a classic isostere of carboxylic acid. The data in the columns represent: Mol is the query chemical with the bioisostere attached. R1 is the bioisostere. biosterDist Bioisoster ‘distance' is calculated on the basis of five terms, two are knowledge-based and three are physicochemical. They are also reflected by the corresponding bars in the column Score BAR. Score BAR: For the bar display the terms are transformed into 0-1 range so that 1 corresponds to best match/identity. Sel - selectivity, as estimated from frequency of replacement of query R- group by a retrieved substituent relative to total number of cases where this substituent replaces any -R group in the database Spec - specificity, as estimated by the difference in activity between a database compound with a retrieved substituent and least active example of a different substituent (on the same scaffold and target) in the database HBD - factor reflecting difference in the number of HB donor functionalities of the retrieved substituent and query -R group HBA - factor reflecting difference in the number of HB acceptor functionalities of the retrieved substituent and query -R group Vol - factor reflecting difference in volume of the retrieved substituent and query -R group scfldAttach indicates the atom(s) and it's hybridization in the original group attachment. It can be used to filter solutions in the query.

If you double click on a row in the table it will show specific examples of a particular substitution from ChEMBL.

7.9.2 3D Bioisostere

The receptor/ligand complex structures from the PDB contains relevant (bioactive) 3D conformation and the environment of the isosteric moieties. This can be used to find 3D bioisosteres. You can watch a Bioisostere Webinar which explains how the 3D database was constructed.

To find 3D Bioisosteres:

Step 1: Read in a chemical into a chemical table. Right click Chemistry/Find Bioisosteres for a Group.

Step 2: Left click and drag over the group you wish to find a 3D bioisostere for and then click OK.

Step 3: The results table will be displayed the nPocs (number of pockets) column is a good indicator of a good bioisostere. As this is the number of times this replacement is seen in the PDB.

Step 4: Click on any of the hits to view specific pair examples in 3D.