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<h2 align="center">Advanced Skills</h2>
<hr>
<ol>
<li><a href="#subject_1">How to build the "seed"
structure?</a></li>
<li><a href="#subject_2">How to set the chemical viability
rules in the parameter file?</a></li>
<li><a href="#subject_3">How to edit the building-block
fragment library?</a></li>
<li><a href="#subject_4">How to edit the forbidden
substructure library?</a></li>
<li><a href="#subject_5">How to edit the toxic substructure
library? </a></li>
<li><a href="#subject_6">How to resume a former job of GROW
or LINK?</a></li>
</ol>
<hr>
<h4><a name="subject_1"><font color="#0000FF">1. How to build the
"seed" structure?</font></a></h4>
<p> Either GROW or LINK needs a seed
structure as the starting point for building up ligand molecules.
For this version of LigBuilder, we do not provide a program to
generate the seed structure automatically although in technique
it is possible. According to our own experience on drug design
and discovery, the expertise and the creativity of the researcher
is most important. So we deliberately avoid providing an
automatic procedure to generate the seed structure in order not
to mislead the user to believe that computer-aided drug design is
simply running a program and then waiting for the results. By
letting the user choose the seed structure, it introduces much
flexibility into the application of LigBuilder.</p>
<p> Choosing a proper seed structure is very
important because all the resultant molecules are the derivatives
of the seed structure. Therefore, it will be ideal if the seed
structure holds the key feature of the prospective ligands. For
example, it may form significant interactions with the target
protein; or it is a proper spatial framework; or it is a good
starting point for organic synthesis. There could be so many
smart ways to choose one seed structure. For example, you may
start form a relevant crystalline complex structure. There must
be some chemical groups on the ligand which exhibit important
interactions with the protein. You can extract them as the seed
structure. Or if you have got a lead compound anyway, you can
tailor it and then dock it into the binding pocket as the seed
structure. Or you can dock some small groups, such as ammonia,
formaldehyde, benzene, and etc., into the binding pocket as the
seed structure. The seed structure could be as large as a
"common" molecule or, in principle, as small as just
one heavy atom, such as methane. </p>
<p> The seed structure is presented in a Mol2
file. Please notice that all the valences on the seed structure
must be fulfilled. Hydrogen atoms should be added. You are
assumed to label "<font color="#0000FF">growing sites</font>"
on the seed structure by simply change the atom type of the
corresponding hydrogen atoms from "<font color="#0000FF">H</font>"
to "<font color="#0000FF">H.spc</font>". You can do
this in the Sybyl graphics interface or edit the Mol2 file
manually. The program will take all the special hydrogen atoms,
i.e. "<font color="#000000">H.spc</font>", on the seed
structure as growing sites. Fragments will be added to these
growing sites to generate new molecules.</p>
<p> The seed structure for running GROW is
assumed to contain only one piece of chemical fragment. So it is
relatively simple to prepare. However, the seed structure for
running LINK often contains several pieces of chemical fragments.
So please be careful: place each fragment in a
"reasonable" way and leave enough space between them.
Labeling growing sites on each fragment will increase the chance
of successful linking.</p>
<p> Please make sure that the seed structure is
positioned at the right place inside the binding pocket.
LigBuilder will not perform either docking or optimization on the
seed structure.</p>
<p> These concepts may confuse you
especially when you are using LigBuilder for the first time. You
are suggested to study the sample seed structures included in the
directory "<font color="#0000FF">example</font>".</p>
<hr>
<h4><font color="#0000FF">2</font><a name="subject_2"><font
color="#0000FF">. How to set the chemical viability rules in the
parameter file?</font></a></h4>
<p> In recent years, some empirical rules for
evaluating the "drug-likeness" of a compound have been
proposed. Maybe the most popular approach is the so-called
Lipinski rules (<em>Adv. Drug. Delivery. Rev. 1997, 23, 3-25</em>).
According to the Lipinski rules, poor absorption or permeation
are more likely when: </p>
<ul>
<li>molecular weight is over 500.</li>
<li>LogP is over 5.</li>
<li>there are more than 5 H-bond donors (the sum of OHs and
NHs).</li>
<li>there are more than 10 H-bond acceptors (the sum of Os
and Ns).</li>
</ul>
<p> Thus if a molecule violates the above
rules, it is not likely to be a successful lead compound. In
LigBuilder, we have set similar parameters to control the
chemical viability of the generated molecules. You are encouraged
to edit these chemical rules to meet your own purpose. The
following key words will appear in the parameter file for GROW or
LINK.</p>
<p> "<font color="#0000FF">APPLY_CHEMICAL_RULES</font>":
apply chemical viability rules or not. It could be "<font
color="#0000FF">YES</font>" or "<font color="#0000FF">NO</font>".
If it is switched on, only molecules which meet all the following
criteria will be collected into <font color="#000000">LIGAND_COLLECTION_FILE</font>.
A molecule violates any of these rules will be rejected.
"YES" is highly recommended.</p>
<p> "<font color="#0000FF">MAXIMAL_MOLECULAR_WEIGHT</font>":
maximal molecular weight.</p>
<p> "<font color="#0000FF">MINIMAL_MOLECULAR_WEIGHT</font>":
minimal molecular weight.</p>
<p> "<font color="#0000FF">MAXIMAL_LOGP</font>":
maximal LogP value. </p>
<p> "<font color="#0000FF">MINIMAL_LOGP</font>":
minimal LogP value.</p>
<p> LigBuilder calculates LogP values using the
<font color="#FF0000">XLOGP v2.0</font> algorithm. For more
detailed description of this algorithm, please refer to: <a
href="xlogp2.pdf">Wang, R.; Gao, Y.; Lai, L. "Calculating
partition coefficient by atom-additive method", <em>Perspectives
in Drug Design and Discovery</em>, <strong>2000</strong>, <em>19</em>,
47-66</a>.</p>
<p> "<font color="#0000FF">MAXIMAL_HB_DONOR_ATOM</font>":
maximal number of H-bond donor atoms. Here, a donor atom refers
to any nitrogen or oxygen atom with at least one hydrogen atom
attached, i.e. -OHs or -NHs.</p>
<p> "<font color="#0000FF">MINIMAL_HB_DONOR_ATOM</font>":
minimal number of H-bond donor atoms. </p>
<p> "<font color="#0000FF">MAXIMAL_HB_ACCEPTOR_ATOM</font>":
maximal number of H-bond acceptor atoms. Here an acceptor atom
refers to any nitrogen or oxygen atom with at least one lone
pair.</p>
<p> "<font color="#0000FF">MINIMAL_HB_ACCEPTOR_ATOM</font>":
minimal number of H-bond acceptor atoms. </p>
<p> "<font color="#0000FF">MAXIMAL_PKD</font>":
maximal binding affinity to the target protein. It is presented
in pKd unit.</p>
<p> "<font color="#0000FF">MINIMAL_PKD</font>":
minimal binding affinity to the target protein.</p>
<p> LigBuilder estimates binding affinities
using the <font color="#FF0000">SCORE v2.0 </font>algorithm. For
more detailed description of this algorithm, please refer to: <a
href="score.pdf">Wang, R.; Liu, L.; Lai, L.; Tang, Y.
"SCORE: A new empirical method for estimating the binding
affinity of a protein-ligand complex", <em>J.Mol.Model</em>.,
<strong>1998</strong>, <em>4</em>, 379-394.</a></p>
<p> To be frank, a "proper" set of
these chemical rules will depend on the project you are working
on. But a "general" set could be like this: molecular
weight: 300~600; LogP: 2.00~5.00; Donors: 2~5; Acceptors: 2~5;
predicted pKd: 5~9.</p>
<hr>
<h4><font color="#0000FF">3</font><a name="subject_3"><font
color="#0000FF">. How to edit the building-block fragment
library?</font></a></h4>
<p> As mentioned in the <em>Introduction</em>
section, LigBuilder uses molecular fragments as building-blocks
to build ligands. The default building-block fragment library
employed by LigBuilder is stored in the directory "<font
color="#0000FF">fragment.mdb</font>". This library contains
nearly 60 fragments, including most of the common chemical groups
and ring frameworks observed in organic compounds. Each fragment
is presented in a Mol2 file. All the fragments have been
pre-minimized.</p>
<p> There is a file named as "<font
color="#0000FF">INDEX</font>" in that directory listing the
contents of the building block library. You can edit this file to
determine which fragment will be used in the ligand construction
and which will not. The format of "<font color="#000000">INDEX</font>"
is like this:</p>
<p><font size="2" face="Courier New">
1 frag_01.mol2 1.00
methane<br>
2
frag_02.mol2 0.50 ethane<br>
3
frag_03.mol2 0.00 propane<br>
</font> ......</p>
<p> Here each line describes one fragment. The
first column is the ID of the fragment. Each fragment must has
its unique ID number. The second column is the name of the
corresponding Mol2 file. The third column is the "<font
color="#000000">acceptability</font>" of the fragment. The
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