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last column is the name of the fragment.</p>
<p> The funny part is the "<font
color="#0000FF">acceptability</font>". This value should be
between 0 and 1. If it is set to 1.00, the fragment is fully
accepted for the ligand construction; if it is set to 0.00, the
fragment is fully rejected. So what if the value is between 0 and
1? In fact, every time when LigBuilder tries to extract a certain
fragment, the program will generate a random number between 0 and
1 and compare this number with the acceptability of that
fragment. If the random number is smaller than the acceptability,
the fragment will be extracted. Otherwise, it will be rejected.
Thus you can control the occurrence of a certain fragment in the
generated molecules simply by modifying its acceptability.</p>
<p> Although the default building-block library
contains various fragments, according to our own experience, in
most cases you do not need all of them. In another word, please
use only necessary fragments to build your molecules. This will
save computational time and make the resultant molecules less
"fancy". You can let the program to neglect the
unwanted fragments by setting their acceptabilities to 0 in the
INDEX file. We strongly recommend you to do this before running
GROW or LINK.</p>
<p> Of course you are not limited in using the
default building-block library. You can also add new fragments to
the library. What you need to do is: (i) build the fragment and
save it in a Mol2 file; (ii) copy the file into the directory
"<font color="#000000">fragment.mdb</font>"; (iii) add
a new line in file "<font color="#000000">INDEX</font>"
to define the fragment. A more ambitious attempt is to build your
own fragment library. This might be helpful when you try to
design a special combinatorial library. In this case, what you
need to do is simply assembling all your fragments into a
directory and create the "<font color="#000000">INDEX</font>"
file under that directory.</p>
<p> While building your own fragment, please
notice that the fragment must be presented as a complete
molecule: <font color="#FF0000">all valences should be filled and
hydrogen atoms should be added.</font> The geometry of the
fragment should be minimized because LigBuilder will not do this.
It will be ideal if the fragment is rigid. If you have to include
rotatable single bonds in the fragment, please provide the
"typical" conformation of that fragment. But if you
like, you can also save several conformations of the same
fragment in different Mol2 files and label them as different
fragments.</p>
<p> Do not forget to set at least one <font
color="#000000">growing site</font> on the fragment. You can do
it by changing the atom type of the corresponding hydrogen atom
from "<font color="#0000FF">H</font>" to "<font
color="#0000FF">H.spc</font>". The simplest way is to set
all the hydrogen atoms on the fragment as growing sites. You can
also choose to assign only some of the hydrogen atoms as growing
sites. By doing so, your can add your expertise of organic
synthesis to the ligand construction. </p>
<p> Another special note should be addressed
here. Actually each fragment in the building-block library is
treated not as a "specific" fragment but rather a
template. While building the ligand molecules, LigBuilder will
perform mutations on the structure whenever it is necessary to
improve the binding affinity. Carbon, nitrogen and oxygen atoms
with the same hybridization state are allowed to mutate to each
other. For example, the "benzene" in the library
actually represents benzene itself and other hetero-substituted
six-membered aromatic rings. This strategy frees the user from
employing numerous fragments to represent chemical structures.</p>
<p align="center"><font size="3"><img src="mutate.gif"
width="285" height="165"></font></p>
<p align="center"><font color="#0000A0">Each fragment in the
building-block library is actually a template</font></p>
<p> We will highly appreciate it if you have
developed your own building-block fragment library and are
willing to share it with other LigBuilder users. Please send us a
copy of your library and we will add it to the LigBuilder package
and distribute it to the public.</p>
<hr>
<h4><font color="#0000FF">4</font><a name="subject_4"><font
color="#0000FF">. How to edit the forbidden substructure library?</font></a></h4>
<p> While building up the molecules, LigBuilder
has some built-in rules to avoid "bad structures", such
as -O-O-, -N-O-, -N-N-, and etc. But this may not be enough for
generating reasonable lead compounds. Therefore, LigBuilder could
also use a built-out, user-maintainable fragment library as a
supplement. We call it "<font color="#0000FF">forbidden
substructure library</font>". While building up the ligand
molecules, the program will check each molecule to judge whether
it contains any substructure defined in the forbidden
substructure library. If so, this molecule will be rejected. </p>
<p> The parameter "<font color="#0000FF">APPLY_FORBIDDEN_STRUCTURE_CHECK</font>"
in the parameter file (for GROW and LINK) determines whether to
apply such checking. It could be "<font color="#0000FF">YES</font>"
or "<font color="#0000FF">NO</font>". </p>
<p><font color="#0000FF"> </font>LigBuilder has
provided a default forbidden substructure library. This library
is stored at directory "<font color="#0000FF">forbidden.mdb</font>".
Each substructure is presented in a Mol2 file. There is also a
file named "<font color="#0000FF">INDEX</font>" under
that directory which lists the contents of the library. The
format of the index file is just the same as the one for "<font
color="#0000FF">fragment.mdb</font>". You can edit that file
to determine which substructure will be used in forbidden
substructure checking and which will not. Please notice that if
the <font color="#0000FF">acceptability</font> of a certain
structure is set to 1.00, it means that this structure will be
used in checking and thus is fully forbidden in the resultant
molecules. On the contrary, if the acceptability is set to 0.00,
it means that the structure will not be used in checking and thus
could exist in the generated molecules. Here we do not recommend
you to set an acceptability between 0 and 1 because it is rather
weird (what does it mean if you do so?).</p>
<p> You will find that the default forbidden
substructure library contains only a dozen of structures because
we believe it should be left open to you (you may have much more
brilliant ideas than we do). You are encouraged to add new
forbidden substructures to the library. To do so, firstly you
should build the structure and save it in a Mol2 file. Then
please copy it to the directory storing the library and add a
line in the "<font color="#000000">INDEX</font>" file
to define this new structure. This process is the same as the one
for adding a fragment to the building-block fragment library. Of
course this time you do not have to assign growing sites on your
molecules.</p>
<p> We will highly appreciate it if you have
developed your own forbidden substructure library and are willing
to share it with other LigBuilder users. Please send us a copy of
your library and we will add it to the LigBuilder package and
distribute it to the public.</p>
<hr>
<h4><font color="#0000FF">5</font><a name="subject_5"><font
color="#0000FF">. How to edit the toxic substructure library? </font></a></h4>
<p> One of the on-going projects in our lab is
studying the structure-toxicity relationship of the organic
compounds. We have analyzed the<font color="#000000"> Registry of
Toxic Effects of Chemical Substances (RTECS, C2 96-4)</font>
database and derived nearly 80 chemical structures which tend to
be toxic. For more detailed description of this work, please
refer to: <a href="toxic.pdf">Wang, J.; Lai, L.; Tang, Y.
"Structural features of toxic chemical for specific
toxicity", <em>J.Chem.Inf.Comput.Sci.</em>, <strong>1999</strong>,
<em>39</em>, 1173-1189.</a></p>
<p> These structures has been summarized as the
"<font color="#0000FF">toxic substructure library</font>".
It is saved in the directory "<font color="#0000FF">toxicity.mdb</font>".
The parameter "<font color="#0000FF">APPLY_TOXIC_STRUCTURE_CHECK</font>"
in the parameter file (for GROW and LINK) determines whether to
apply toxic substructure checking. It could be "<font
color="#0000FF">YES</font>" or "<font color="#0000FF">NO</font>".
If it is switched on, those molecules containing any toxic
substructures will not be collected in the resultant virtual
library.</p>
<p> Of course you are also free to edit this
library. Each structure is presented in a Mol2 file. There is
also a file named "<font color="#0000FF">INDEX</font>"
under that directory which lists the contents of the library. The
format of the index file is just the same as the one for "<font
color="#0000FF">fragment.mdb</font>" or "<font
color="#0000FF">forbidden.mdb</font>". You can edit that
file to determine which structure will be used in toxic
substructure checking and which will not. Please notice that if
the <font color="#0000FF">acceptability</font> of a certain
structure is set to 1.00, it means that this structure will be
used in checking and thus is fully forbidden in the resultant
molecules. On the contrary, if the acceptability is set to 0.00,
it means that the structure is not used in checking and thus
could exist in the resultant molecules. Here we do not recommend
you to set an acceptability between 0 and 1.</p>
<p> You can also add new structures to this
library. To do so, firstly you should build the structure and
save it in a Mol2 file. Then please copy it to the directory
storing the library and add a line in the "<font
color="#000000">INDEX</font>" file to define this new
structure. In fact, you are not restricted in considering only
toxicity. Other properties which are important for lead
discovery, such as chemical stability, can also been counted. You
just add anything that you think is not proper for a potential
lead compound to this library.</p>
<p> We will highly appreciate it if you have
developed your own library and are willing to share it with other
LigBuilder users. Please send us a copy of your fragment library
and we will add it to the LigBuilder package and distribute it to
the public. </p>
<hr>
<h4><font color="#0000FF">6</font><a name="subject_6"><font
color="#0000FF">. How to resume a former job of GROW or LINK?</font></a></h4>
<p> After GROW or LINK has done the job, the
program will save the final population in a file specified by the
keyword "<font color="#0000FF">POPULATION_RECORD_FILE</font>"
in the parameter file. This file is in LigBuilder LIG format. If
you want to resume your former job, you can simply set that file
as "<font color="#0000FF">SEED_LIGAND_FILE</font>" for
a new job. The program will understand this and resume the GA
procedure directly on the population saved in that file. This
strategy may be useful when you want to or have to do the job
step by step. </p>
<hr>
<p align="center"><a href="index.html">[Content]</a> <a
href="intro.html">[Introduction]</a> <a href="download.html">[Download]</a>
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[Skills] <a href="faq.html">[FAQs]</a></p>
<p align="center"><font size="2"><em>(These web pages are edited
by Dr. Renxiao Wang. Latest update: August, 2000)</em></font></p>
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