Chemistry Reference
In-Depth Information
Rush
et al
[30] described the first application of ROCS (Rapid Overlay of
Chemical Structures, an OpenEye Scientific Software) in order to find new
scaffolds for small molecular inhibitors of an antibacterial target. This
implemented method for scaffold hopping uses an algorithm that finds the greatest
amount of overlap between two 3D molecules. It is based on the entire volume of
the molecule and not only on the surface. The emphasis and purpose of this
approach is to identify molecules from databases that can adopt very similar
shapes to the query molecules, thus, increasing chances of scaffold hopping. The
database used contain molecules with molecular weights between 180 and 400
Da, less than nine rotatable bonds, molecules with only one chiral center, logD
lower than 4 and less than 4 ionizable groups. These molecules were increased to
a set of 3D conformers using the OMEGA software. Thus, two new scaffolds
were found and they were significantly different for the proposed target using this
algorithm. The active compounds were identified without any reference to the
chemistry details of known active compounds. The ROCS approach is based on
an intuitive fragmentation based on physicochemical reasoning of the known
active compounds to generate appropriate models for the searches. This is what
differs from other 3D search methods. The experimental results presented in this
study validated the use of ROCS for scaffold hopping, and suggest that its
application for the purpose of identifying new compounds is of great interest in
drug discovery.
As one of the main tools used for scaffold hopping, virtual screening has received
widespread attention because it is a technique often used in drug discovery
programs. For this, a screening is performed in a large database of potential
compounds for drug candidates targeting a protein or a reference molecule to
subsequently select a subset of compounds for experimental testing. For the
prominence of virtual screening methods to successfully run scaffold hopping,
many descriptors have been developed to measure its effectiveness [31].
A complementary program to the ROCS program is EON (an OpenEye Scientific
Software) for electrostatic potential calculations. EON is a descriptor used for
scaffold hopping, it calculates the similarity of two pre-aligned molecules based
on their electrostatic fields. That is, the overlaps and alignments of pairs of
molecular structures made by ROCS, EON calculates the electrostatic field
