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Small Molecule Drug
Discovery
Methods, Molecules
and Applications
Andrea Trabocchi
Department of Chemistry "Ugo Schiff"
University of Florence
Sesto Fiorentino, Florence
Italy
Elena Lenci
Department of Chemistry "Ugo Schiff"
University of Florence
Sesto Fiorentino, Florence
Italy
Elsevier
Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
Copyright © 2020 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopying, recording, or any information
storage and retrieval system, without permission in writing from the publisher. Details on
how to seek permission, further information about the Publisher’s permissions policies
and our arrangements with organizations such as the Copyright Clearance Center and the
Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright
by the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional
practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described
herein. In using such information or methods they should be mindful of their own safety
and the safety of others, including parties for whom they have a professional
responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or
editors, assume any liability for any injury and/or damage to persons or property as a
matter of products liability, negligence or otherwise, or from any use or operation of any
methods, products, instructions, or ideas contained in the material herein.
ISBN: 978-0-12-818349-6
xi
xii Contributors
The discovery of new drugs is an endeavor of high scientific demand and societal
relevance. It requires interdisciplinary research spanning the life sciences, chemis-
try, pharmcology, and even material science. It benefits mankind because the treat-
ment of disease is one of societies’ most urgent demands to science.
Among the pharmacopoeia available to us, small molecules historically are most
prevalent, and they form the largest group of new chemical entities in medicinal
chemistry research to this very day. Undoubtedly biologicals, in particular anti-
bodies, have gained major importance and are here to stay, but it is also evident
that small molecule drugs will remain to be of highest relevance in drug discovery
in the foreseeable future.
Hence the science that underlies the discovery and development of new bioactive
small molecules that can be considered drug candidates and that may inspire new
approaches to the treatment of disease is of utmost importance and calls for contin-
uous introduction of new methods and principles.
This necessity underlies the articles compiled in the book edited by Andrea Tra-
bocchi and Elena Lenci. Collectively the authors shine light on a very impressive
ensemble of some of the most relevant topics in contemporary medicinal chemistry
and drug discovery. These include chemical synthesis, cheminformatics, and bio-
physical and computational methods and highlight individual case studies focusing
on some of the greatest challenges in this science, as for instance Alzheimer disease.
The Editors have chosen the topics wisely and with deep insight into drug dis-
covery. Thereby the book not only gives an overview of recent developments, it
also guides the reader to the frontiers of medicinal chemistry research. It will be
both entertaining to read and educative such that it will be of interest to the profes-
sional skilled in the art, as well as to newcomers to the field, in particular, advanced
graduate and postdoctoral students.
I hope that this book will find widespread interest from practitioners in medicinal
chemistry and simply curious scientists trying to get a glimpse at and an understand-
ing of the science that drives small molecule drug discovery.
Herbert Waldmann
Max Plank Institute of Molecular Physiology
Dortmund, Germany
September 2019
xiii
Preface
iminosugars within the field of carbohydrates. Chapter 8 outlines the synthesis and
structural features of small molecules characterized by spiroacetal moiety, and
Chapter 9 reports the case study of centrocountins as nature inspired indoloquinoli-
zines. The third part contains two selected case studies about the successful applica-
tion of small molecules in biomedical research. Chapter 10 deals with PPIs as
therapeutic targets for anticancer drug discovery and describes the case study of
MDM2 and BET bromodomain inhibitors, and Chapter 11 is an account of the dis-
covery of small molecules for the treatment of Alzheimer disease.
These presentations have been conceived for a broad readership and should in-
terest not only those readers who currently work in the field of organic and medicinal
chemistry addressing drug discovery, but also those who are considering this
approach in the field of chemical biology, taking advantage of the use of small mole-
cule as chemical probes for dynamically interrogating biological systems and for
investigating potential drug targets. We hope these Chapters will stimulate further
advances in the ever-developing field of small molecule drug discovery.
Andrea Trabocchi
Elena Lenci
Florence, September 2019
Abbreviations
xvii
xviii Abbreviations
PS Polystyrene
PSSC Protein structure similarity clustering
PTP1B Protein-tyrosine phosphatase 1B
PUMA Platform for Unified Molecular Analysis
PVDF Polyvinylidene difluoride
QSAR Quantitative structureeactivity relationship
RB Rose bengal
RBs Rotatable bonds
RCM Ring closing metathesis
RF Random forest
RGD Arg-Gly-Asp
RIfS Interference spectroscopy
RNA Ribonucleic acid
ROC Receiver operating characteristics
ROCS Rapid Overlay of Chemical Structures
ROM Ring opening metathesis
ROS Reactive oxygen species
RTV Ritonavir
RU Response units
RXR Retinoid X receptor
SAR Structureeactivity relationship
SBS Society for Biomolecular Sciences
SBVS Structure-based virtual screening
ScFv Single-chain variable fragment
SCONP Structural classification of natural products
SDS-PAGE Sodium dodecyl sulfate-polyacrylamide gel electrophoresis
SE Shannon entropy
sEH Soluble epoxide hydrolase
SET Single electron transfer
SGLT2 Sodium-glucose linked transporter 2
SHG Second harmonic generation
SIFt Structural interaction fingerprint
SLL Small lymphocytic lymphoma
SlogP Octanol/water partition coefficient
SMM Small molecule microarray
SOCE Store-operated calcium entry
SOMs Self-organizing maps
SPOS Solid-phase organic synthesis
SPR Surface plasmon resonance
SPRs Structureeproperties relationships
SPS Solid-phase synthesis
SRR Single reactant replacement
SQV Saquinavir
STAT3 Signal transducers and activators of transcription 3
STD Saturation transfer difference
SVM Support vector machines
t-SNE Distributed stochastic neighbor embedding
TASK3 TWIK-related acid-sensitive K þ channel 3
Abbreviations xxiii
Synthetic approaches
toward small molecule
libraries 1
Elena Lenci, Andrea Trabocchi
Department of Chemistry “Ugo Schiff”, University of Florence, Sesto Fiorentino, Florence, Italy
1.1 Introduction
Drug discovery is the long and arduous process that can eventually bring molecules
from the laboratories to the market. Although the number of new approved drugs
showed about a 30% increase over 2017, marking a new record after 1996 [1], in
general only 1 molecule out of 5000 hit candidates can reach the market [2].
The process of discovering, testing, and gaining approval for a new drug has
changed a lot during the last century. From the isolation of active ingredients
from traditional remedies and natural products, drug discovery has evolved into a
multidisciplinary and complex process that brings together the efforts of biologists,
pharmacologists, and chemists. Many different approaches nowadays can be applied
in drug discovery. From one hand, the rational design of ligands remains the “gold
standard” in medicinal chemistry, especially when the biological target is well
defined and structurally known (Fig. 1.1, top) [3]. On the other hand, a parallel
new approach has emerged, especially in those fields, such as cancer and neurode-
generative disorders, where the biological target or the mode of binding is not well
known [4,5], or difficult to study in traditional drug discovery programs [6].
FIGURE 1.1
Comparison between conventional target-based and chemical genetics drug discovery
approaches.
When researchers are experiencing this impasse, one alternative, for the discov-
ery of new targets and new lead compounds, is the application of large small mol-
ecules libraries in high-throughput screening (HTS), phenotypic assays, and
chemical genetics studies (Fig. 1.1, bottom) [2,7e10]. The relevance of this
approach is also highlighted by the emergence of international screening initiatives,
such as EU-OPENSCREEN [11] or the European Lead Factory [12,13].
In both approaches, synthetic chemistry plays a key role in generating high-
quality small molecules collections. In fact, despite the vast success of the biological
drugs (monoclonal antibodies or recombinant proteins), the favorable pharmacoki-
netic properties of small molecules libraries allowed them to remain as the gold stan-
dard for the development of new medications, especially in the case of enzyme
inhibitors. In fact, among the 59 new drugs approved by the FDA in 2018, 42 are
small molecules and only 17 are biologic drugs [1]. In Table 1.1 are reported, for
example, the 11 small molecules approved by the FDA as new drugs for cancer ther-
apy in 2018.
Table 1.1 Small molecules approved by the FDA as new drugs for cancer
therapy in 2018.
Name Structure Company Biological effect
Encorafenib Array BRAF inhibitor.
Used in combination with
binimetinib for the
treatment of BRAF-
mutated melanoma
Table 1.1 Small molecules approved by the FDA as new drugs for cancer therapy in
2018.dcont’d
Name Structure Company Biological effect
Glasdegib Pfizer Hedgehog (hh) signaling
pathway inhibitor. Used in
the treatment of acute
myeloid melanoma
Duvelisib Verastam Phosphoinositide-3-
kinase (PI3K) inhibitor.
Used in the treatment of
chronic lymphocytic
leukemia or small
lymphocytic lymphoma
Larotrectinib Bayer and Tropomyosin receptor
Loxo kinase (TRK) A/B/C
inhibitor. Used in the
treatment of solid tumors
that have the neurotrophic
receptor tyrosine kinase
gene fusion
Lorlatinib Pfizer ATP-competitive inhibitor
of anaplastic lymphoma
kinase (ALK) and c-Ros
oncogene 1 (Ros)1. Used
in the treatment of ALK-
positive metastatic non
esmall cell lung cancer
Dacomitinib Pfizer Covalent ligand of human
epidermal growth factor
receptors Her-1, Her-2,
and Her-4. Used in the
treatment of metastatic
nonesmall cell lung
cancer
Apalutamide Janssen Androgen receptor (AR)
antagonist. Used in the
treatment of prostate
cancer
Thus, to address this demand, very powerful synthetic methods are necessary for
the generation of large small molecules libraries. Several efforts have been devoted
to improve the quality and quantity of small molecules representing a library. In
particular, during last decades, organic chemists have taken advantage of high-
throughput synthesis methods, such as solid-phase techniques [14e17], and
combinatorial chemistry [18,19]. Unfortunately, despite the apparent success, these
chemistry approaches have not fulfilled the desired expectations as the automation
of discovery processes has proven to be inefficient [20,21]. Thus, new frontiers in
4 CHAPTER 1 Synthetic approaches toward small molecule libraries
the synthesis of small molecules libraries are being explored, with the aim of
improving the quality of the small molecules representing a library, where the syn-
thetic efforts are not guided by a specific core structure, but rather by concepts like
molecular diversity (i.e., diversity-oriented synthesis) and bioactivity or biosynthetic
pathway (i.e., biology-oriented synthesis). This chapter focuses on main synthetic
approaches for the generation of large, high-quality small molecule collections,
with an emphasis on organic synthesis and technical methods rather than assay
results.
Table 1.2 First 15 small molecules of top 200 most prescribed drugs in
2018.
Name Structure Biological effect
Lisinopril ACE inhibitor, used in the
treatment of hypertension and
symptomatic congestive heart
failure
Continued
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