Virtual Screening for RNA-Interacting Small Molecules - Biophysical Approaches to Translational Control of Gene Expression - page 232

free energy force field based on a Lamarckian genetic algorithm, to bring about
speedy prediction of conformation with calculated free energies of association
(Morris et al. 1998 ). This program has application in X-ray crystallography, struc-
ture-based drug design, virtual screening, and protein-protein interaction studies.
DOCK was introduced by the Kuntz group at UCSF and uses a rigid body docking
algorithm and flexible ligand docking algorithm to dock the ligand into a negative
image of the binding pocket (Ewing et al. 2001 ). FlexX is a fully automatic com-
puter program for predicting protein-ligand interaction. FlexX can predict not only
the lowest energy geometry of the complex of ligand with protein but also the bind-
ing affinities using an empirical scoring function (Böhm 1994 ) . The descriptions of
other widely used docking programs including commercial and free softwares are
listed in Table 12.1 .

12.2 Computational Programs to Predict 2D

and 3D RNA Structures

In recent years, while the number of identified RNA sequences has rapidly increased,
the number of known 3D structures has not kept pace with it. For this reason, there is
a large gap between the number of known RNA sequences and 3D structures. For
example, tRNA is one of the most structurally well characterized RNAs and its
1,101,833 characterized sequences are reported in the Rfam (Gardner et al. 2009 ) , a
database of sequence families of structural RNAs; however, only 170 structures are
reported. To apply structure-based drug design approaches to the identification of RNA
binding ligands, computational programs are required for prediction of RNA struc-
tures. Several computer programs have been developed for folding of RNA secondary
structures, and modeling of RNA 2D and 3D structures. Those computational tools are
summarized in Tables 12.2 and 12.3 .

12.3 RNA-Targeted Virtual Screening

Many clinical antibiotics including macrolides, aminoglycosides, and others target-
ing bacterial ribosomal RNA (rRNA) reveal that RNA is the important target for
drug development (Knowles et al. 2002 ; Hermann 2005 ) . The appearance of drug
resistance is the most critical problem in treating bacterial (Neu 1992 ) and viral
infections (Perrin and Telenti 1998 ). RNAs contain highly conserved structural and
functional motifs that may serve as drug targets, so the development of resistance to
drugs targeting RNA can be slower than that to drugs targeting protein (Gallego and
Varani 2001 ). In contrast to DNA, which mostly has a double-stranded helix struc-
ture, RNA is generally single-stranded and folds into complex 3D structures that
provide unique pockets for small molecules (Foloppe et al. 2006 ) , thus making
RNA an attractive drug target.