Small Molecule Drug Discovery

Methods, Molecules and Applications

Andrea Trabocchi, Elena Lenci

• Publisher: Elsevier
• Year: 2019
• ISBN:
  9780128183502
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

Small Molecule Drug Discovery: Methods, Molecules and Applications presents the methods used to identify bioactive small molecules, synthetic strategies and techniques to produce novel chemical entities and small molecule libraries, chemoinformatics to characterize and enumerate chemical libraries, and screening methods, including biophysical techniques, virtual screening and phenotypic screening. The second part of the book gives an overview of privileged cyclic small molecules and major classes of natural product-derived small molecules, including carbohydrate-derived compounds, peptides and peptidomimetics, and alkaloid-inspired compounds. The last section comprises an exciting collection of selected case studies on drug discovery enabled by small molecules in the fields of cancer research, CNS diseases and infectious diseases.

The discovery of novel molecular entities capable of specific interactions represents a significant challenge in early drug discovery. Small molecules are low molecular weight organic compounds that include natural products and metabolites, as well as drugs and other xenobiotics. When the biological target is well defined and understood, the rational design of small molecule ligands is possible. Alternatively, small molecule libraries are being used for unbiased assays for complex diseases where a target is unknown or multiple factors contribute to a disease pathology.

• Outlines modern concepts and synthetic strategies underlying the building of small molecules and their chemical libraries useful for drug discovery
• Provides modern biophysical methods to screening small molecule libraries, including high-throughput screening, small molecule microarrays, phenotypic screening and chemical genetics
• Presents the most advanced chemoinformatics tools to characterize the structural features of small molecule libraries in terms of chemical diversity and complexity, also including the application of virtual screening approaches
• Gives an overview of structural features and classification of natural product-derived small molecules, including carbohydrate derivatives, peptides and peptidomimetics, and alkaloid-inspired small molecules

Chapter 1

Synthetic approaches toward small molecule libraries

Elena Lenci, and Andrea Trabocchi Department of Chemistry “Ugo Schiff”, University of Florence, Sesto Fiorentino, Florence, Italy

Abstract

The drug discovery process is long and arduous, as it is estimated that the chance for a new molecule to reach the market as a rug is only 1:10,000. Thus, there is a need of a high number of small molecules, which differ not only for the appendages, but also for the molecular skeleton, to increase the chance of finding new lead compounds. From the birth of medicinal chemistry as a scientific discipline in 1930 to our days, organic chemists have developed a large variety of different synthetic methods to improve the quality and quantity of small molecules representing a library. In this chapter, the main methods are described, spanning through solid-phase techniques, combinatorial chemistry, diversity-oriented synthesis, and biology-oriented synthesis, with an emphasis on historical perspective and comparative evaluations.

Keywords

Chemical libraries; Combinatorial chemistry; Diversity-oriented synthesis; Drug design; Drug discovery; Molecular complexity

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 neurodegenerative 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 discovery of new targets and new lead compounds, is the application of large small molecules libraries in high-throughput screening (HTS), phenotypic assays, and chemical genetics studies (Fig. 1.1, bottom) [2,7–10]. 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 pharmacokinetic properties of small molecules libraries allowed them to remain as the gold standard 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 therapy 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
Binimetinib		Array	MEK1/2 inhibitor. Used in combination with Encorafenib for the treatment of BRAF mutated melanoma
Talazoparib		Pfizer	Poly (ADP-ribose) polymerase type 1 and 2 inhibitor. Used in the treatment of BRCA-mutated HER2-negative breast cancer
Ivosidenib		Agios	Isocitrate dehydrogenase type 1 (IDH1) inhibitor. Used in the treatment of acute myeloid melanoma
Gilteritinib		Astellas	FLT3, AXL, and ALK kinases inhibitor. Used in the treatment of acute myeloid melanoma
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 Loxo	Tropomyosin receptor 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–small 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 non–small 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 smal...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Foreword
• Preface
• Abbreviations
• Chapter 1. Synthetic approaches toward small molecule libraries
• Chapter 2. Chemical reactions for building small molecules
• Chapter 3. Chemoinformatics approaches to assess chemical diversity and complexity of small molecules
• Chapter 4. Virtual screening of small-molecule libraries
• Chapter 5. Screening and biophysics in small molecule discovery
• Chapter 6. Principles and applications of small molecule peptidomimetics
• Chapter 7. sp2-Iminosugars as chemical mimics for glycodrug design
• Chapter 8. Synthesis and biological properties of spiroacetal-containing small molecules
• Chapter 9. Centrocountins—synthesis and chemical biology of nature inspired indoloquinolizines
• Chapter 10. PPIs as therapeutic targets for anticancer drug discovery: the case study of MDM2 and BET bromodomain inhibitors
• Chapter 11. Discovery of small molecules for the treatment of Alzheimer’s disease
• Index