Computational Drug Discovery and Design

Chapter 8

Fragment-Based Ligand Designing

Shashank P. Katiyar, Vidhi Malik, Anjani Kumari, Kamya Singh,

and Durai Sundar

Abstract

Fragment-based drug design strategies have been used in drug discovery since it was first demonstrated
using experimental structural biology techniques such as nuclear magnetic resonance (NMR) and X-ray
crystallography. The underlying idea is that existing or new chemical entities with known desirable proper-
ties may serve both as tool compounds and as starting points for hit-to-lead expansion. Despite the recent
advancements, there remain challenges to overcome, such as assembly of the synthetically feasible struc-
tures, development of scoring functions to correlate structure and their activities, and fine tuning of the
promising molecules. This chapter first covers the theoretical background needed to understand the
concepts and the challenges related to the field of study, followed by the description of important protocols
and related software. Case studies are presented to demonstrate practical applications.

Key words3D QSAR, De novo, Fragment growing, Fragment linking, High-throughput screening,

Ligand-based drug design, Structure-based drug design

1 Introduction

Fragment-based drug discovery has shown its potential with the

success stories of development of some early inhibitors like uroki-

nase inhibitors, p38 MAP kinase inhibitors, cyclic nucleotide phos-

phodiesterases inhibitors, and HSP90 inhibitors [1–4]. Number of

compounds developed by fragment based approach have success-

fully faced the Phase-I clinical trials. Contributing to the list are

(1) a factor Xa inhibitor from Lilly (LY-517717), (2) a Bcl-xL

inhibitor from Abbott (ABT263), (3) kinase inhibitor from Astex

(AT9283), (4) an HSP90 inhibitor from a collaboration between

Novartis and Vernalis (NVP-AUY-922), and (5) a PPAR agonist

from Plexxikon (PLX-204). De novo designing, on the other hand,

despite sharing the common characteristics with fragment-based

drug discovery has not shown same level of success. Many of the

concepts and objectives of de novo are similar to those of fragment-

based. First, both the approaches depend on the small chemical

Mohini Gore and Umesh B. Jagtap (eds.),Computational Drug Discovery and Design, Methods in Molecular Biology, vol. 1762,
https://doi.org/10.1007/978-1-4939-7756-7_8,©Springer Science+Business Media, LLC, part of Springer Nature 2018

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