number of generation, size of population, number of
parent molecules, similarity cutoff, and percentage of elitism
(seeNote 1).
4.Construction of ligand molecule through fragment linking
Fragment linking is useful in case of larger binding site and
involves the covalent linking of two or more fragments, placed
at distinct location within same binding pocket, via linkers
[58]. It is a powerful strategy for optimizing low affinity frag-
ment molecules into high affinity lead molecules. However, it is
difficult to obtain same binding mode of both fragments in the
final optimized product because of limitations of linker mole-
cule [59]. Similar toGROWmodule,LINKmodule of Lig-
Builder also uses seed structure to construct lead molecule but
unlikeGROW, seed structure forLINKconsist of more than
one small fragment. These fragments are linked byLINKinto
single heavy molecule having higher affinity with target pro-
tein.LINKalso uses genetic algorithm for evolution of frag-
ments into drug-like molecule by linking them with different
linker molecules. Simple command line to runLINKis:#link link_parameter-file.indexParameter file forLINKincludes same constraints as the
one described forGROW(see Note 2). Ligand molecules
generated byLINKandGROWare reported in LIG file of
LigBuilder (seeNote 3).3.3 Evaluation
of Physicochemical
and Pharmacokinetic
Properties of Lead
Molecules
The structural and biological properties of the lead molecules must
be evaluated to identify the potential of the lead molecules. The
efforts directed toward creating synthetic molecules have greatly
been aided by the molecular descriptors calculated using various
tools. QikProp is one such prediction program that was developed
by Professor William L. Jorgensen. QikProp predicts descriptors of
physical significance and properties that are pharmaceutically rele-
vant [60]. It also provides with an option to compare the properties
of a molecule with those of already known drugs. Generated struc-
ture of de novo molecule is fed as an input to the QikProp tool.
Running QikProp module generates file containing property data,
structural information, and reference values. Analysis of the
descriptors is done on the basis of the recommended values to
perform screening of the lead compounds.3.4 De novo Ligand
Design Software
Since the advent of de novo drug discovery, many computer pro-
grams have been used to aid the complex process. The main objec-
tive of all the software remains the same; however, their scoring
functions and sampling algorithms vary and keep evolving with
time to come up with an optimal solution between accuracy and
speed. Table1 lists some of the widely used SBDND and LBDND
based de novo software.Fragment-Based Ligand Designing 133