Title:

Similar Molecules Bind in a Similar Fashion

Authors:

Jonas Boström (a)
Anders Hogner (b)
Stefan Schmitt (b)
(a) Department of Medicinal Chemistry, 
(b) GSI Chemical Computing,
AstraZeneca R&D Mölndal, Sweden

Abstract:

A central theme in drug design is to make small modifications to lead molecules
to obtain desired properties, because it is generally assumed that similar 
molecules bind in a similar fashion (the underlying theme of ROCS).

The scope of the current work is to investigate if similar ligands actually
bind in a similar fashion, by analysing experimental data from the protein 
databank (PDB). We also establish some details about the changes (if any) 
to the active sites involved in binding such ligands.

We have searched the complete PDB using Reliscript for pairs of similar ligands
binding to homologous proteins. The manner in which the pairs were retrieved
from the databases will be described. Two compounds are considered to be 
similar if they have a Maximum Common SubStructure (MCSS) Tanimoto 
(TanimotoMCSS) greater than 0.8. 

The TanimotoMCSS is obtained by solving:




where NA and NB are the number of atoms in molecules A and B, respectivly, and
NAB is the the number of atoms in the MCSS of A and B.



where the MCSS is calculated using the algorithm OEChem.


Figure. An example of two molecules having a high TanimotoMCSS

In general we find that if two ligands are similar, then the binding mode 
as defined by the relative orientation in the protein, is conserved.
However, the active sites of proteins binding similar ligands are seldom 
identical, for example differing in; side-chain rotamers, positions of water 
molecules and backbone movements. Data will be presented quantifying these 
differences.We allow ourselves to draw general conclusions from this study 
since our data set spawns a broad spectrum of proteins.

JBostromSimSimCUP.pdf