Bioinformatics Biocomputing - Ercim

SPECIAL THEME: BIOINFORMATICS
Searching for New Drugs in Virtual Molecule Databases
by Matthias Rarey and Thomas Lengauer
The rapid progress in sequencing the human genome
opens the possibility for the near future to understand
many diseases better on molecular level and to obtain
so-called target proteins for pharmaceutical research.
If such a target protein is identified, the search for
those molecules begins which influence the protein’s
Searching for New Lead Structures
The development process of a new
medicine can be divided into three phases.
In the first phase, the search for target
proteins, the disease must be understood
on molecular-biological level as far as to
know individual proteins and their
importance to the symptoms. Proteins are
the essential functional units in our
organism and can perform various tasks
ranging from the chemical transformation
of materials up to the transportation of
information. The function is always
linked with the specific binding of other
molecules. As early as 100 years ago,
Emil Fischer recognised the lock-and-key
principle: Molecules that bind to each
other are complementary to each other
both spatially and chemically, just as only
a specific key fits a given lock (see Figure
1). If a relationship between the
suppression (or reinforcement) of a
protein function and the symptoms is
recognised, the protein is declared to be
a target protein. In the second phase, the
actual drug is developed. The aim is to
detect a molecule that binds to the target
protein, on the one hand, thus hindering
its function and that, on the other, has got
further properties that are demanded for
drugs, for example, that it is well tolerated
and accumulates in high concentration at
the place of action. The first step is the
search for a lead structure - a molecule
that binds well to the target protein and
serves as a first proposal for the drug.
Ideally, the lead structure binds very well
to the target protein and can be modified
such that the resulting molecule is suitable
as a drug. In the third phase, the drug is
transformed into a medicine and is tested
in several steps to see if it is well tolerated
and efficient. The present paper is to
discuss the first step, ie the computerbased
methods of searching for new lead
structures.
New Approaches to Screening
Molecule Databases
The methods of searching for drug
molecules can be classified according to
two criteria: the existence of a threedimensional
structural model of the target
protein and the size of the data set to be
searched. If a structural model of the
protein is available, it can be used directly
to search for suitable drugs (structurebased
virtual screening); ie we search for
a key fitting a given lock. If a structural
model is missing, the similarity to
molecules that bind to the target protein
is used as a measure for the suitability as
a drug (similarity-based virtual
screening). Here we use a given key to
search for fitting keys without knowing
the lock. In the end, the size of the data
set to be searched decides on the amount
of time to be put into the analysis of an
individual molecule. The size ranges from
a few hundred already preselected
molecules via large databases of several
millions of molecules to virtual
combinatorial molecule libraries
theoretically allowing to synthese of up
to billions of molecules from some
hundred molecule building blocks.
The key problem in structure-based
virtual screening is the prediction of the
relative orientation of the target protein
and a potential drug molecule, the socalled
docking problem. For solving this
problem we have developed the software
tool FlexX [1] in co-operation with
Merck KGaA, Darmstadt, and BASF AG,
Ludwigshafen. On the one hand, the
difficulty of the docking problem arises
from the estimation of the free energy of
a molecular complex in aqueous solution
and, on the other, from the flexibility of
the molecules involved. While a sufficient
description of the flexibility of the protein
presumably will not be possible even in
the near future, the more important
activity specifically and which are therefore
considered to be potential drugs against the disease.
At GMD, approaches to the computer-based search
for new drugs are being developed (virtual screening)
which have already been used by industry in parts.
flexibility of the ligand is considered
during a FlexX prediction. In a set of
benchmarks tests, FlexX is able to predict
about 70 percent of the protein-ligand
complexes sufficiently similar to the
experimental structure. With about 90
seconds computing time per prediction,
the software belongs to the fastest docking
tools currently available. FlexX has been
marketed since 1998 and is currently
being used by about 100 pharmaceutical
companies, universities and research
institutes.
If the three-dimensional structure of the
target protein is not available, similaritybased
virtual screening methods are
applied to molecules with known binding
properties, called the reference molecule.
The main problem here is the structural
alignment problem which is closely
related to the docking problem described
above. Here, we have to superimpose a
potential drug molecule with the reference
molecule so that a maximum of functional
groups are oriented such that they can
form the same interactions with the
protein. Along the lines of FlexX, we have
developed the software tool FlexS [2,3]
for the prediction of structural alignments
with approximately the same performance
with respect to computing time and
prediction quality.
If very large data sets are to be searched
for similar molecules, the speed of the
alignment-based screening does not
suffice yet. The aim is to have comparison
operations whose computation takes by
far less than one second. Today linear
descriptors (bit strings or integral vectors)
are usually applied to solve this problem.
They store the occurrence or absence of
characteristic properties of the molecules
such as specific chemical fragments or
short paths in the molecule. Once such a
descriptor has been determined, the linear
10 ERCIM News No. 43, October 2000