EON calculates the electrostatic similarity between two small molecules in the form of an Electrostatic Tanimoto (ET) score. Given a query molecule and a set of interesting molecules (ROCS overlay hits, for example), EON will calculate the Electrostatic Tanimoto between each database molecule and the query. Note that EON does not perform any overlay or alter the input orientation of the structures. They must be pre-aligned to the query on input. Also, since electrostatics calculations require high quality partial charges, EON will calculate new partial charges for the input structures using MMFF94. If the user provides an input file that contains structures with higher-quality partial charges, EON can use them as well.
EON is also dependent on pKa state and formal charges as these have a significant impact on electrostatics. EON now has the ability to adjust both the query and database molecule to a neutral pH model. This feature is on by default, but can be turned off by using appropriate command line flags.
Since electrostatics overlays are very dependent on alignment and require a good quality alignment between query and database molecule, ROCS provides the best input to EON. However, electrostatic complementarity is more dependent on subtle conformational changes than shape is, so there are several steps that can be taken to ensure the best possible success with EON.
Firstly, one can ensure that ROCS outputs multiple interesting conformers
per molecule. ROCS includes a flag
that allows generation of a multi-conformer set of ROCS-aligned output
specifically for input into EON. This file can be generated in parallel
with a ROCS hit list so that in a single ROCS run you can find ROCS hits
and prepare EON input. Please see the ROCS documentation for more
detail on these flags.
Secondly, EON reads one or more conformers from the input file and uses technology from OMEGA to expand terminal torsions to search for subtle changes in conformation that might increase the score without changing the overall shape overlap with the query. To score just the input conformers and not search for alternate terminal conformations, the -scoreonly flag is provided.
Part of understanding EON results is visualization of the electrostatic grids used in the calculation. Although off by default, when writing EON results to a binary (OEB) file, ET grids can be attached to each molecule and visualized using the EON View mode in VIDA.
Since EON calculations can be time-consuming (approximately 1 molecule per second per CPU), EON can use the same distributed computing technology, Open MPI, that ROCS uses to help distribute the workload across a cluster of machines.