Computational Drug Discovery and Design

perform single point calculation as the geometry of the frag-

ment is already known [52].The combination of 6-31G(d) set

[53] and B3LYP method [54] is also used for hybrid function.

5.Execution of symmetry operation

In order to maintain the symmetry for the fragment plane

and to account for errors, the operation is done on the atomic

coordinates with their point charges.

6.Solvent treatment for simulation studies

Either continuum dielectric, cosimulated explicit water

molecules or solvent correction factor that is based on the

solvation energies can be used for treatment of the solvent.

This specific solvent correction procedure is aimed to simulate

the fragments in vacuo.

7.Creation of category field for the fragment

Extraction of the fragments from the library is facilitated by

adding various labels to categorize the fragments.

8.Storage of fragment in the database

Depending on the compatibility of the software used for

simulation studies of the fragment–protein complex, the frag-

ments are stored in the database in specific formats.

3.2 Screening
of Fragment Libraries
and Developing Leads
Through Fragment
Growing or Linking

After preparation of fragment libraries, the next step in the SBDND

is to analyze the binding pocket of target protein in order to build a

pharmacophore model and develop seed structures for construc-

tion of potential lead molecules. Experimentally determined high-

resolution structure of target molecule is a prerequisite to carry out

binding pocket analysis. If cocrystallized structure of protein–li-

gand complex exists, then it is an ideal structure to start with for

fragment library screening. In the absence of experimentally solved

structure, computational techniques can be employed to model the

structure of protein based on homology with crystal structures

deposited in PDB (Protein Data Bank) [55]. Though various soft-

ware are available for carrying out binding site analysis and genera-

tion of seed structure, we describe the different modules of

LigBuilder that can be used for the same [56]:

1.Binding pocket analysis of the target protein

Binding pocket analysis should not only aim at defining the

shape of the protein but also its hypothetical key interaction

sites. It should specify hydrogen bond acceptor, hydrogen

bond donor and hydrophobic interaction sites that can be

used to develop pharmacophore model. Derived pharmaco-

phore model can be used as a query structure for fragment

screening.POCKETis one of the modules of LigBuilder that is

designed to analyze the binding pocket of protein and generate

pharmacophore model of protein binding site. It uses a com-

mand line prompt and requires a parameter file as input that

Fragment-Based Ligand Designing 131