Computational Drug Discovery and Design

hypotheses but also enables to secure intellectual property rights

and in the identification of new molecules significantly eliciting a

response to targets which till now have not been the focus of drug

discovery efforts. The classes of computational methods for the de

novo design are mentioned below [3–6]:

(a) Fragment

positioning

methods

Identifies a specific position of atom or fragment in

binding sites

(b) Site point

connection methods

Identifies a unique site location for placing

fragments in the binding sites

(c) Fragment

connection methods

Connects the fragments at particular position

within binding sites

(d) Library

construction

methods

Builds a library of fragments with desirable

information

(e) Molecule growth

methods

Keep atoms or fragments at different places within

binding sites of target and growing them by

joining with other atoms/fragments with

various coordinations

(f) Random

connection methods

Connect the fragments in random way

For fruitful candidate design, three paradigms acknowledged

by de novo design program are (1) structure construction of the

candidate compounds (atom/fragment based), (2) evaluation of

the molecule class, i.e., its fitness (based on 3D receptor-ligand

docking and scoring or ligand-based similarity measure) and

(3) methodically examining the search space or difficulty of optimi-

zation (based on depth-first/breadth first search, evolutionary

algorithms, exhaustive structure enumeration). These constitute

the modern de novo design approach to implement the chemical

structure generation process [7, 8].

Complete data linked to ligand receptor interaction forms the

primary target constraintsfor the candidate compounds as these

input are used in scoring the property evaluation of the generated

structures. The designed compound with some target affinity and

drug-likeness is proposed. Clusters of the virtual structures are

accompanied by simulated organic synthesis steps in order to

draw prospective synthesis route for each generated structures.

Shape constraints and noncovalent ligand–receptor interactions

especially the hydrogen bonding forms the principal interaction

site [9]. Atom-based or fragment-based methods are used to

assemble the molecules based on the receptor interaction sites.

Fragment-based approach narrows the search space effectively.

Moreover, if fragment molecules frequently arise in drug molecules

then drug-likeness of designed compounds will be high. Fragments

72 Venkatesan Suryanarayanan et al.