Small Molecule Drug Discovery: Methods, Molecules and Applications

Description

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 discoveryProvides modern biophysical methods to screening small molecule libraries, including high-throughput screening, small molecule microarrays, phenotypic screening and chemical geneticsPresents 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 approachesGives an overview of structural features and classification of natural product-derived small molecules, including carbohydrate derivatives, peptides and peptidomimetics, and alkaloid-inspired small molecules Small Molecule Drug Discovery: Methods, Molecules and Applications Copyright Contributors Foreword Preface Abbreviations 1. Synthetic approaches toward small molecule libraries 1.1 Introduction 1.2 What is a small molecule? 1.3 Historical perspective 1.4 Drugs from natural products 1.5 Rational design of small molecule drugs 1.6 Combinatorial chemistry and DNA-encoded libraries 1.7 Diversity-oriented synthesis 1.8 Biology-oriented synthesis 1.9 Conclusions and future outlook References 2. Chemical reactions for building small molecules 2.1 Introduction 2.2 Cross-coupling reactions 2.2.1 Palladium-mediated cross-couplings: applications in DOS, SPOS, and combinatorial synthesis 2.2.2 Other metal-mediated cross-couplings and their applications 2.2.2.1 Olefin metathesis in SPOS and DOS 2.2.3 Nickel-mediated cross-couplings: recent advances 2.2.4 Copper, iron, and gold catalyzed reactions: the future in cross-coupling chemistry 2.3 Cycloaddition reactions 2.4 Multicomponent reactions 2.5 Photochemical processes 2.6 Late-stage functionalizations 2.7 Conclusions and outlook References 3. Chemoinformatics approaches to assess chemical diversity and complexity of small molecules 3.1 Introduction 3.2 Diversity analysis 3.2.1 Methods to evaluate chemical diversity 3.2.1.1 R-group decomposition (qualitative) 3.2.1.2 Molecular diversity 3.2.1.3 Structural fingerprints 3.2.1.4 Alignment analysis 3.2.1.5 Scaffold diversity 3.2.1.6 Consensus diversity analysis: Consensus Diversity Plots 3.2.2 Visual representation of chemical diversity 3.3 Molecular complexity 3.3.1 Methods to evaluate chemical complexity 3.4 Combining diversity and molecular complexity 3.5 Conclusions and future directions References 4. Virtual screening of small-molecule libraries 4.1 Introduction 4.2 Structure-based virtual screening 4.2.1 Molecular docking 4.2.2 Scoring functions 4.2.3 Implementations and tools 4.2.4 Sources of 3D target structure 4.3 Ligand-based virtual screening 4.3.1 2D fingerprint similarity searching 4.3.2 3D shape-based screening 4.3.3 Pharmacophore-based matching 4.4 Small-molecule libraries for virtual screening 4.4.1 Sources of small-molecule libraries 4.4.2 Preparation of small-molecule libraries for virtual screening 4.4.3 Filter druglike/leadlike molecules 4.5 In silico validation of virtual screening 4.6 Postscreening process 4.7 Perspective References 5. Screening and biophysics in small molecule discovery 5.1 Introduction 5.2 Background and scope 5.2.1 Screening technology 5.2.2 Chemical technology (compounds) 5.2.3 Promiscuous behavior 5.2.4 Scope 5.3 Biophysical methods used in HTS 5.3.1 Fluorescence polarization 5.3.2 Förster (fluorescence) resonance energy transfer 5.3.3 Time-resolved FRET 5.3.4 AlphaScreen 5.3.5 Differential scanning fluorimetry 5.3.6 Encoded library technology 5.4 Biophysical methods used for hit validation 5.4.1 Light scattering 5.4.2 Interaction analysis 5.4.2.1 Surface plasmon resonance 5.4.2.2 Biolayer interferometry 5.4.2.3 Second harmonic generation 5.4.3 Nuclear magnetic resonance 5.4.3.1 Ligand-detected nuclear magnetic resonance 5.4.3.1.1 1H saturation transfer difference 5.4.3.1.1 1H saturation transfer difference 5.4.3.1.2 Proton relaxation methods 5.4.3.1.2 Proton relaxation methods 5.4.3.2 Protein-detected chemical shift perturbation 5.4.4 Isothermal titration calorimetry 5.4.5 Mass spectrometry 5.4.5.1 Cellular thermal shift assay 5.4.6 Affinity selection-mass spectrometry 5.4.6.1 Hydrogen-deuterium exchange 5.4.6.2 Disulfide trapping 5.4.7 Microscale thermophoresis 5.5 Structural methodologies 5.5.1 X-ray crystallography 5.5.2 Cryogenic electron microscopy 5.6 Case study using biophysical methods in concert to discovery small molecule stabilizers of the 14-3-3/estrogen receptor complex References 6. Principles and applications of small molecule peptidomimetics 6.1 Introduction 6.2 Definition and classification 6.3 Strategic approaches to peptidomimetic design 6.3.1 Local modifications 6.3.1.1 Amide bond surrogates 6.3.1.2 Side chain modifications 6.3.1.3 Cα- and N-alkylation of amino acids 6.3.1.4 Nα-Cα cyclized amino acids 6.3.1.5 Constraining the side chain rotational freedom 6.3.2 Global restrictions 6.4 Peptidomimetic molecules 6.4.1 Dipeptide isosteres 6.4.2 Transition-state isosteres 6.4.3 Retroinverso peptides 6.4.4 Azapeptides 6.4.5 Peptoids 6.4.6 The triazole ring as a peptide bond isostere 6.5 Secondary structure peptidomimetics 6.5.1 α-Helix mimetics 6.5.2 β-Sheets mimetics 6.5.3 β-Turn mimetics 6.6 Application of peptidomimetics as protease inhibitors 6.6.1 A case study of peptidomimetic drugs: HIV protease inhibitors 6.7 Conclusion References 7. sp2-Iminosugars as chemical mimics for glycodrug design 7.1 Introduction 7.2 sp2-Iminosugars as antiproliferative and antimetastatic agents 7.3 sp2-Iminosugars in cancer immunotherapy 7.4 sp2-Iminosugars as antileishmanial candidates 7.5 sp2-Iminosugars and Inflammation 7.6 Concluding remarks References 8. Synthesis and biological properties of spiroacetal-containing small molecules 8.1 Introduction 8.2 Biological relevance of the spiroacetal moiety 8.3 Versatile synthetic methods for accessing spiroacetals 8.4 Synthesis of libraries of spiroacetal-containing small molecules 8.4.1 Spiroacetal derivatives as potential chemotherapeutic agents for the treatment of CLL leukemia 8.4.2 Spiroacetal derivatives as modulator of tubulin cytoskeleton integrity and phosphatase inhibitors 8.4.3 Spiroacetal derivatives as potential therapeutic agents for the treatment of oxidative stress–related pathologies 8.5 Conclusion and future directions References 9. Centrocountins—synthesis and chemical biology of nature inspired indoloquinolizines 9.1 Introduction 9.2 Synthesis of natural product-inspired Tetrahydroindolo[2,3-a]quinolizines 9.3 Phenotypic screening and discovery of centrocountins as novel mitotic inhibitors 9.4 Identification and confirmation of cellular targets of Centrocountin-1 9.5 Conclusion References 10. PPIs as therapeutic targets for anticancer drug discovery: the case study of MDM2 and BET bromodomain inhibitors 10.1 Introduction 10.2 The case study of the p53-MDM2 PPI inhibitor APG-115 10.3 Development of the BET bromodomain ligand I-BET762 10.4 Inhibitors of PPIs in clinical trials 10.5 Conclusion References 11. Discovery of small molecules for the treatment of Alzheimer’s disease 11.1 Introduction 11.2 Small molecules as multitargeting ligands multitarget-directed ligands 11.2.1 Quinone derivatives 11.2.2 Selenazolone derivatives 11.2.3 Stilbene derivatives 11.2.4 Hydroxyanthraquinone derivatives 11.2.5 Indole derivatives 11.2.6 Melatonin (N-acetyl-5-methoxytryptamine) derivatives 11.2.7 Coumarin derivatives 11.2.8 Phenothiazine and phenoselenazine derivatives 11.2.9 Pyrimidinylthiourea derivatives 11.2.10 Quinazoline and pyrido[3,2-d]pyrimidine derivatives 11.2.11 Thiazole derivatives 11.2.12 Tadalafil derivatives 11.2.13 Pyridothiazole derivatives 11.2.14 Benzyloxyphenylpiperazine derivative 11.2.15 Quinoline-indole derivatives 11.3 Conclusions and future directions References Index A B C D E F G H I K L M N O P Q R S T U V X