depth-first search’, ‘Monte Carlo and Metropolis criterion’ and
‘Evolutionary algorithms’ [36, 39, 43, 44].
After the briefings on the concepts of de novo drug designing,
protocols and software related to de novo drug design are defined
further in this chapter.3 Methodology
In silico drug designing methods are not restricted by the con-
straints that govern experimental approaches. The combination of
both these methods has led to the discovery of many lead mole-
cules. The strategy of drug discovery involves execution of multi-
step computational approaches (Fig.1). Although many software
based on different algorithms are available, here we discuss only
selected widely popular software (MacroModel, LigBuilder, Qik-
Prop, etc.) used in representative steps of structure-based in silico
drug designing process.3.1 Construction
of the Fragment
Libraries
Thorough sampling of the chemical space is highly dependent on
the fragments present in the library. Hence, successful lead genera-
tion requires construction of quality fragment libraries. Designing a
good fragment library depends on a number of factors like diversity,
complexity, selectivity, reactivity, solubility, and efficiency of the
fragments. Computational steps involved in generation of fragment
library are discussed below:1.Selection of the two-dimensional atomic structure of the fragment
While selecting the 2D structure of the virtual fragments,
various points must be taken into account. There should be no
significant change in the properties of the fragment when it is
made a part of the molecule. Commercial availability of syn-
thetic intermediates or synthetic feasibility of the fragment
must be ensured. Sometimes, known ligands are deconstructed
as components for creating fragments.
2.Generation of the three-dimensional conformers
Use of rigid fragments during simulation studies of the
same gives rise to the need of generating multiple 3D structures
as the atomic structures are usually flexible [45]. Selection of
2D structure should be in a way that it has minimum number of
rotatable bonds eliminating the requirement of many simula-
tions due to large number of conformers. MacroModel has a
system conformational search module used for this purpose
[46]. After identification of conformers, energy minimization
of structure coordinates is performed.
3.Assignment of force field atom types to fragment atoms
The simulations of fragment–protein complex make use of
molecular mechanics force field. Hence, designating force fieldFragment-Based Ligand Designing 129