- Chemically advanced template search (CATS) for scaffold
hopping. - AutoDock Vina 1.1.2 for molecular docking.
- Gromacs 4.5.5 to study the dynamic stability of the docked
compounds.
3 Methods
The basic idea of general process of de novo drug design using
computational approaches has been presented here for the devel-
opment of potentially effective inhibitor against vascular endothe-
lial growth factor receptor-2 (VEGFR-2) tyrosine kinase
[23, 24]. Besides, some of designed compounds through de novo
design software are listed in Table1. In the past couple of years,
many of de novo design packages have been created with more
futuristic arts in drug discovery and development, represented in
Table2. In addition, some more facts could be utilized for better
enhancement of de novo design approaches (seeNotes 1and 2 ).3.1 Generation
of VEGFR-2 Tyrosine
Kinase Inhibitors Using
De Novo Design
Strategy
3.1.1 Preliminary
Requirements
Here, a case study of de novo designed inhibitors for the biological
target vascular endothelial growth factor receptor-2 (VEGFR-2)
tyrosine kinase using LigBuilder V2.0 is presented, which utilizes
fragment-based algorithm for constructing new chemical inhibi-
tors. The X-ray crystallographic coordinates of human VEGFR-
2 tyrosine kinase domain with pyrrolopyrimidine inhibitor was
retrieved from the Protein Data Bank (PDB code: 3VHE) [23].3.1.2 Preprocessing
of Targeted Protein
Preprocessing of targeted protein was successfully employed to
assign missing hydrogens, for removing unnecessary water mole-
cules and for the separation of protein–ligand along with charge
calculation by Gasteiger using Chimera 1.9, and also for adding
the missing residues and side chains by Modeller 9.15 [78, 79]
(seeNote 3).3.1.3 Binding Site
Prediction and Ligand
Generation
The design of the fresh ligand is based on the active site information
in the 3D structure of receptor. LigBuilder V2.0 [60], which is a
cavity detection method, was utilized to determine the binding
sites. Next the LigBuilder V2.0’s function “Extract” was carried
out to generate the seeds in the form of pyrrolo[3,2-d]pyrimidine,
benzene, and urea from the original ligand. Finally, the linking
mode strategy of BUILD was applied to create new designs of
molecules from prepositioned to positioned seed structure with
different pieces. This process was continued until all the fragments
in each piece were linked by rational bonds into a single molecule.
Later the evaluation of protein–ligand binding affinity using an74 Venkatesan Suryanarayanan et al.