Nov 28 2022
16.11 Fragment Linking Core Replacement
This feature finds the best scaffold replacement or linker fragment from a
database. It lets you interactively select two or more points of connection or
replacement and search for possible fragments in the 3D database (SDF or Molsoft
local database MOLT). The cutting bonds used to define scaffold are matched
against a 3D database with a certain RMSD cutoff (usually very small). The best
superposition is taken for the original compound and the chemical is minimized.
The result is returned as a standard Ligand Editor hit list where results can be easily browsed, sorted and compared. Linker prediction can be made in the presence or absence of the receptor. Filters such as energy strain, maximum number of rotatable bonds and contact distance to the receptor can be used.
| Step 1: Setup the ligand and/or the receptor in the 3D ligand editor. If you have fragments already made you should select the fragments and then choose "Selection" in the drop down menu
in the ligand setup step. If you do not wish for the receptor to be considered when sampling linkers then just setup the ligand only. Once the ligand and/or receptor are setup it is generally a good idea to minimize the ligand to remove any clashes and optimize the geometry.
| Step 2: Once the ligand and/or the receptor has been setup click on the edit tools button. A panel of editing tools will be displayed, click on the scissors button. Mark two or more bonds using the scissors
tool. The first click on the bond will assign some direction (which should point the part you want to preserve), second click inverts the direction, third click clears the mark. For bonds to the hydrogen or bonds to the terminal heavy atom only one possible direction is available. |
| Step 3: Select the Advanced button and choose the option Find Linker. A dialog window will be displayed as shown above which has three tabs.
- Conformation Database - You can choose to screen one ore more SDF files containing 3D coordinates or a molt file that is stored locally on your machine or on MolCart. You can download databases in molt format here https://molsoft.com/addons/conf/
- Linker Database Scan - This is an inbuilt database of linkers that you can filter and screen.
- Local Table Scan - If you have your own database of linkers with two attachment points you can use this option to screen it. An attachment point on a chemical is represented by an asterisk.
Screening using the Conformation Database Tab
You can choose to screen one ore more SDF files containing 3D coordinates or a molt
file that is stored locally on your machine or on MolCart.
- Provide a path to the 3D SDF or Molt file. We have provided some examples of 3D conformer databases here https://molsoft.com/addons/conf/
- Strain Cutoff - any ligand exceeding this Strain value will not be placed in the results table. If you are using a ligand directly from the PDB it is a good idea to minimize the ligand and check the
initial strain or increase this cutoff.
- Max Rot Bonds in the Core - any ligand exceeding this number of rotatable bond value will not be placed in the results table.
- Contact with Receptor CutOff - any ligand exceeding this distance will not be placed in the results table. This value is significant if the receptor is included in setup.
- Use APF Score this will give you a Score (lower the better) about how well the linker matches the Atomic Property Field 3D pharmacophore of the current linker.
- The use pharmacophore filter allows you to match linkers with a pharmacophore object. These are physical pharmacophore points positioned in 3D Learn how to make a 3D pharmacophore object here.
Screening using the Linker Database Scan Tab
A database of linkers is provided with the ICM distribution - you can screen them using this tab. There are also filtering options avaialable in the panel on the right hand side.
Screening using the Local Table Scan Tab
This option allows you to screen your own table of linkers. The linkers must have two attachment points defined by an asterisk.
| Step 4: Once the fragment fitting has completed a table of results will be displayed. The table is ranked by strain with the top hit in row 1. You can browse the hits using the toggle buttons in the "L" column.
- Strain is the energy strain of the ligand.
- Score2 is the same value as strain (possible place holder for future release).
- RMSD - is the RMSD to the original fragment before linker connection.
Three Point Core Replacement Three cores can be linked by selecting them with the scissors button as shown in Step 1 above. Number of hits will be significantly lower then in 2 point replacement because the extra anchor adds some restraint. We recommend to use larger database for the search (e.g. chembridge100K.molt ) and make sure that ligand is minimized before searching.