Craig Plot and Topliss

Scheme
Dr. Supriyo Saha
 Craig Plot
The Craig plot, named after Paul N. Craig, is a plot of two substituent
parameters (e.g. Hansch-Fujita π constant and sigma constant) used in
rational drug design.
• The Craig plot was quite simple but efficient approach to the
identification of bioisosteric substituents.
• Two most used forms of a Craig plot are
 plotting the sigma constants of the Hammett equation versus
hydrophobicity.
plotting the steric terms of the Taft equation against hydrophobicity.
• Allows an easy identification of suitable substituents for a QSAR
analysis which includes both relevant properties
• Choose a substituent from each quadrant to ensure orthogonally.
• Choose substituents with a range of values for each property
 Topliss Scheme
• Topliss scheme is the stepwise way to choose the right parent
molecule, right side chain and procedure.
• Topliss schemes are three types
 To choose right aromatic substituent
 To Choose right side Chain
 To choose batch wise procedure to develop a lead molecule.
• Key features:
• Maximize the chances to generate most potent compound
• Choose the perfect substituents such as electrostatic, hydrophobic or
steric
• Choose the ideal scheme to choose the right scaffold or target.
• Topliss Tree – Aromatic Substitution
 The Topliss tree is a simple stepwise process for phenyl group
optimization.
Chances are, most of your hits start with a phenyl group, substituted
phenyl, or related heterocyles.
By making a few compounds sequentially following the Topliss tree,
you can quickly identify a more potent tool compound for use in
protein co-crystallization or a functional assay.
 The preliminary SAR this generates also helps prioritize your many
hits and identify which compounds have no rational SAR and are
likely just assay interference compounds.
The Topliss tree works based on the
fundamental assumption that there are three
broad properties that a substituent may
change about a compound:
hydrophobicity (p),
electronics (σ), and steric (Es). 

A previous post about LogD illustrated why hydrophobicity can contribute to binding affinity, and another
previous post illustrated many subtle aromatic interactions where one would expect electronic effects to
make a difference.  By following the Topliss tree, you’re quickly sampling this three-dimensional property
 Topliss Tree – Side Chain
• There’s also a handy scheme for alkyl side chains in Topliss’s 1972
article, based on similar principles.
• This scheme works in the same way as the previous aromatic
substitution scheme.
• This scheme can be used to follow up on compounds containing a
methyl group in the previous scheme, and the aromatic scheme can be
used to follow up on compounds containing a phenyl group resulting
from this side chain scheme.
 The Topliss Batchwise Method

• If the parallel synthesis of new analogues is straightforward, it can be

faster to use the Topliss batchwise method.
• Here, instead of making one compound at a time, you start by making
and testing a group of five compounds (including the unsubstituted
phenyl compound). 
• Then rank order the compounds by potency, and based on the rank
ordering, choose a second compound group to synthesize.
• Based on the same principles as the Topliss tree, this batchwise
approach usually leads to analogs with increased potency quickly.