Do similar ligands bind in a similar fashion?

COMP 223

Jonas Boström1, Anders Hogner2, and Stefan Schmitt, Stefan.Schmitt@astrazeneca.com2. (1) Department of Medicinal Chemistry, AstraZeneca R&D Mölndal, 43183 Mölndal, Sweden, (2) GSI Chemical Computing, AstraZeneca R&D Mölndal, 43183 Mölndal, Sweden
A central theme in drug design to obtain desired properties in lead molecules is to make small, incremental modifications since it is generally assumed that similar molecules bind in a similar fashion to the protein. The scope of the current work is to investigate this general belief, by analyzing the protein databank (PDB) for pairs of similar ligands complexed to the binding sites of the same biological target. The manner in which the pairs were retrieved from the databases will be described and a similarity metric, based on maximum common substructures is introduced. Our findings indicate that for two similar ligands the binding mode, as defined by the relative orientation in the protein, is conserved. However, the binding sites for similar ligands in the same biological target are seldom structurally identical, e.g. they differ in side-chain rotamers, water positions and backbone movements. Data will be presented quantifying these differences.

Poster Session -- Sponsored by Novartis Institutes for BioMedical Research
6:00 PM-8:00 PM, Tuesday, 30 August 2005 Washington DC Convention Center -- Hall A, Poster

8:00 PM-10:00 PM, Monday, 29 August 2005 Washington DC Convention Center -- Hall A, Sci-Mix

Division of Computers in Chemistry

The 230th ACS National Meeting, in Washington, DC, Aug 28-Sept 1, 2005