Computational Drug Discovery and Design

Molecular Operating Environment (MOE). This was achieved by

altering the linking group between the two aromatic rings and at

the same time substituting one of the carboxylic groups with

Michael’s acceptor. The next step is to dock these molecules into

the binding site which was done using the software FLEXX. The

scoring was done on the potential of the molecule to interact with

the two arginine residues and to situate the vinyl ketone in such a

position that it is in close proximity to Cys431. The best structures

were presented with:

1. Michael’s acceptor located 5 A ̊ away from the sulfur atom of
   Cys431.


2. Addition of side chain with more interaction sites.

Further, to assess the stability of the protein–ligand complex

MDS was performed. The 1 ns simulation presented with a rela-

tively stable interaction. On the other hand it was observed that

there was steric hindrance due to the presence of aromatic ring

which led the compound to drift away from Cys431 almost 6–7 A ̊.

Hence a smaller heterocycle ring was needed to be found that could

replace benzene. Moreover in MDS it was observed that the linker

side chain was not beneficial, hence was detached in later molecules.

Finally, a pyrrole derivative was chosen as a potential inhibitor. The

structure presented following key interactions:

1. Formation of H bond between ester moiety and R393.


2. Formation of H bond between Arg481 and the carbonyl group
   of the vinyl ketone.


3. In MDS distance between the sulfur of Cys431 and the
   Michael’s acceptor of<4A ̊was found to be stable.


4. Formation of H bond between NH of pyrrole and carbonyl
   group of Val432 acted as a stabilizing factor.

The compound was synthesized to evaluate its activity in heli-

case assay.

5 Summary

Fragment based or de novo drug designing has proven to be an

indispensable tool in tedious and complex process of drug discov-

ery. In the past decade, computational de novo methods have

evolved to aid the process for time and cost saving. Computational

fragment screening provides an effective investigation of the chem-

ical space, and identification of more valuable hits as compared to

the traditional screening approach. Computational methods over-

come the limitations of the experimental approach by avoiding the

need of material, solubility concerns, and higher time and cost, but

140 Shashank P. Katiyar et al.