Protein-Protein Interactions: Pathophysiological and Therapeutic Aspects: Volume II

Preface
Acknowledgments
Contents
About the Authors
1: Protein Networks in Human Disease
	1.1 Introduction to Genetic Basis of Disease
	1.2 Classical Protein Complexes in the Cell
	1.3 Characterization of Disease-Related Mutations at Protein Interaction Interfaces
	1.4 Role of Protein Interactions in Disease
	1.5 Impact of Protein Interaction Networks on Analysis of Disease Genes: A Case Study
		1.5.1 Potential Therapeutic Drug Targets in COVID-19
		1.5.2 Drug Repurposing Strategy
	1.6 Intrinsic Disorder-Based Human Diseases
	1.7 PPIs in GPCR-Related Diseases
	1.8 PPIs Related to Cataract Formation
		1.8.1 Etiology of Cataract
	1.9 PPIs Involved in Cystic Fibrosis
	1.10 PPIs in Ubiquitin-Proteasome Pathway
	1.11 PPIs in MODY (Maturity Onset Diabetes of the Young) Family
	1.12 Conclusion
	References
2: Protein-Protein Interactions in Cancer
	2.1 Introduction to Cancer
	2.2 Profiling PPIs of Single Cancer Cells
	2.3 Building Cancer Cell Maps
	2.4 OncoPPI Portal
	2.5 PPIs Between Growth Factors/Chemokines and Their Receptors
	2.6 PPIs for Cytoskeleton Dynamic Pathways
	2.7 Ras-Raf Interactions
		2.7.1 Ras Protein
		2.7.2 Raf Kinases and Other Ras Effectors
		2.7.3 Prevalence of Ras and Raf Protein in Cancer
		2.7.4 Therapeutic Targeting of Ras-Raf Interactions
	2.8 PKA Signalosome
	2.9 Myc-Max Interactions
	2.10 p53-MDM2 Interactions
	2.11 Wnt/β-Catenin
	2.12 Nuclear Receptor (NR)
	2.13 X-Linked Inhibitor of Apoptosis Protein (XIAP)/Caspase-9
	2.14 HSP90/Cdc37
	2.15 Bax/Bcl-2
	2.16 Splicing Factor 3b (SF3B)
	2.17 MLL1-WDR5/Menin
	2.18 Alpha/Beta Tubulin
	2.19 Rac 1-GEF
	2.20 Sur2-ESX
	2.21 CDK2/Cyclin A
	2.22 HIF in Cancer
	2.23 CBF in Cancer
	2.24 FAK in Cancer
	2.25 B Cell Lymphoma 6 (BCL-6)
	2.26 Notch Receptors
	2.27 Conclusion
	References
3: Protein-Protein Interactions in Neurodegenerative Diseases
	3.1 Fundamentals of Neurodegeneration
	3.2 Interacting Proteome of Synapse
	3.3 Alzheimer´s Disease (AD)
		3.3.1 Cyclin-Dependent Kinase 5
		3.3.2 Calpains
		3.3.3 Dynamin-Related Protein 1 (Drp1)
		3.3.4 BACE-1
		3.3.5 Munc18-Interacting (Mints) Proteins
		3.3.6 Chemokines
	3.4 Parkinson´s Disease (PD)
		3.4.1 α-Synuclein
		3.4.2 Endophilin-A1 (sh3gl2)
		3.4.3 Cathepsin
		3.4.4 Parkin (PARK2)
		3.4.5 Apolipoprotein E (APOE)
	3.5 Amyotrophic Lateral Sclerosis (ALS)
		3.5.1 TAR DNA-Binding Protein-43 (TDP-43)
		3.5.2 Superoxide Dismutase-1 (SOD1)
		3.5.3 Fused in Sarcoma (FUS)
	3.6 Huntington Disease
		3.6.1 Transcription Factors
		3.6.2 Autophagy-Related Protein
		3.6.3 Cell Division-Related Proteins
		3.6.4 Trafficking Vesicle-Associated Proteins
	3.7 Spinal Muscular Atrophy
		3.7.1 Plastin 3 (PLS3)
		3.7.2 Gemins
		3.7.3 Profilins (PFN)
	3.8 Frontotemporal Dementia (FTD)
		3.8.1 Tau Protein
		3.8.2 Progranulin
		3.8.3 Valosin-Containing Protein (VCP)
		3.8.4 Chromatin-Modifying Protein 2B
		3.8.5 Protein p62
		3.8.6 Ubiquilin-2
			3.8.6.1 TDP43-UBQLN2 Interaction
		3.8.7 TREM2 Protein
		3.8.8 Tank-Binding Kinase 1 (TBK1)
	3.9 Batten Disease (Neuronal Ceroid Lipofuscinosis)
	3.10 Conclusion
	References
4: Protein-Protein Interactions in Immune Disorders and Inflammation
	4.1 Overview of Inflammation
	4.2 Types of Immune Disorders
		4.2.1 Hypersensitivity Disorders
		4.2.2 Immunodeficiency Disorders
		4.2.3 Autoimmune Disorders
	4.3 Multiple Sclerosis
		4.3.1 Myelin Basic Protein (MBP) and Peptidylarginine Deiminases (PADs)
		4.3.2 Fatty Acid-Binding Proteins (FABPs)
		4.3.3 Proteolipid Protein (PLP)
	4.4 Systemic Lupus Erythematosus (SLE)
		4.4.1 Heat Shock Protein (HSP)
		4.4.2 Chemokines
		4.4.3 Calreticulin (CRT)
	4.5 Inflammatory Bowel Disease (IBD)
		4.5.1 Myeloid-Related Protein 8/14 (MRP8/14) and TLR
		4.5.2 NF-E2-Related Factor 2/Kelch-Like ECH-Associated Protein-1
		4.5.3 Haptoglobin (Hp)
		4.5.4 Ring Finger Protein 5/S100A8
	4.6 Type-1 Diabetes (T1D)
		4.6.1 Protein Tyrosine Phosphatase (PTPs)
		4.6.2 Peroxisome Proliferator-Activated Receptors (PPARs)
		4.6.3 Sodium Glucose Transporter (SGLTs)
	4.7 Psoriasis
		4.7.1 TNF-Like Weak Inducer of Apoptosis/Fibroblast Growth Factor-Inducible 14
		4.7.2 Aquaporin-3 (AQP3)
		4.7.3 Caspase Recruitment Domain/Caspase-Recruited Membrane-Associated Protein
	4.8 Rheumatoid Arthritis
		4.8.1 Galectins (GL)
		4.8.2 Connective Tissue Growth Factors (CTGF)
		4.8.3 Calreticulin (CRT)
	4.9 Conclusions
	References
5: Protein-Protein Interactions in Host-Pathogen Interactions
	5.1 Introduction to PPIs in Host-Pathogen Interactions
	5.2 Microbial Pathophysiology
		5.2.1 Adhesion and Invasion of Host System
		5.2.2 Evasion of Host System
		5.2.3 Microbial Proliferation in Host
			5.2.3.1 Intracellular Colonization
			5.2.3.2 Microbial Biofilms
		5.2.4 Immune Responses Against Infection
			5.2.4.1 Features of Host Immune Response
			5.2.4.2 Host-Pathogen Interactions (HPIs) Involving Innate Immune Responses
			5.2.4.3 HPIs Involved in Adaptive Immune Response
			5.2.4.4 Immune Response Via Metabolite Sequestration
	5.3 PPIs in Bacterial Infections
		5.3.1 Bacterial Virulence Factors
			5.3.1.1 Adhesion and Invasion Factors
				Fimbrial Adhesins
				Bacterial Secretion Systems
				Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMMs)
					Collagen-Binding Proteins (CoBPs)
					Fibrinogen-Binding Proteins (FgBPs)
					Fibronectin-Binding Proteins (FnBPs)
				Capsule and Other Surface Components
			5.3.1.2 Bacterial Toxins
				Endotoxins
				Exotoxins
					Cytotoxins
						Glucosylating CytotoxinsGlucosylating Cytotoxins
						Rho-ADP-Ribosylating CytotoxinRho-ADP-Ribosylating Cytotoxin
						Proteolytic CytotoxinsProteolytic Cytotoxins
						GAP-Mimicking CytotoxinsGAP-Mimicking Cytotoxins
					Neurotoxins
						Botulinum ToxinBotulinum Toxin
						Tetanus ToxinTetanus Toxin
					Pore-Forming Toxins (PFTs)
						Colicin FamilyColicin Family
						ClyA FamilyClyA Family
						Hemolysin FamilyHemolysin Family
					Enterotoxins
						Heat-Labile EnterotoxinHeat-Labile Enterotoxin
						Heat-Stable E. coli EnterotoxinsHeat-Stable E. coli Enterotoxins
						Shiga and Shiga-Like EnterotoxinsShiga and Shiga-Like Enterotoxins
						Bacillus EnterotoxinsBacillus Enterotoxins
						Staphylococcal EnterotoxinsStaphylococcal Enterotoxins
			5.3.1.3 Other Proteins Involved in Host-Pathogen Interactions
	5.4 PPIs in Viral Infections
		5.4.1 Viral Capsid Proteins and Their Molecular Partners
			5.4.1.1 Spike Protein and Its Molecular Partners
				Ace2-Spike (SARS) Interactions
				ACE2-Sipke (HCoV-NL63) Interactions
				DPP4-Spike (MERS) Interactions
	5.5 PPIs in Fungal Infections
		5.5.1 HPIs Involved in Candida Infection
			5.5.1.1 HPIs Involving Fungal Invasins: Als3 and Ssa1
			5.5.1.2 HPIs Involving Fungal Enzymes
		5.5.2 Fungal Toxins
	5.6 PPIs in Protozoal Infections
		5.6.1 HPIs Involved in Malaria Pathogenesis
			5.6.1.1 Plasmodium Interaction with Skin and Liver
			5.6.1.2 Plasmodium Interactions in Blood Stages
				Invasion/Exit of Merozoites
				Cytoadherence of Merozoites
	5.7 PPIs in Prion Diseases
		5.7.1 Conformational Features of Prion Proteins
	5.8 Conclusion
	References
6: Drug Design Methods to Regulate Protein-Protein Interactions
	6.1 Introduction
		6.1.1 Challenges to Modulate PPIs
	6.2 Role of Hot Spots in PPIs
	6.3 Identification of Druggable Hot Spots in PPIs
		6.3.1 CASTp
		6.3.2 FTMaP
		6.3.3 FTFlex
		6.3.4 LIGSITE
		6.3.5 Q-Site Finder
		6.3.6 ANCHOR
		6.3.7 Pocket Query
		6.3.8 pyDock
	6.4 Mechanism of Action of PPI Modulators
	6.5 PPI Inhibition Approaches
		6.5.1 Small-Molecule Approach
		6.5.2 Protein-Based Approach
		6.5.3 Peptide/Peptidomimetic-Based Approach
			6.5.3.1 Cyclic Peptides
			6.5.3.2 α-Helix-Constrained Peptides: ``Stapled´´ Peptides
			6.5.3.3 β-Hairpin-Stabilized Peptides
			6.5.3.4 Bicyclic Peptides
			6.5.3.5 β-Peptides
			6.5.3.6 Peptoids
			6.5.3.7 Miniproteins
			6.5.3.8 Photo-Switchable Peptide Inhibitors
			6.5.3.9 Natural Products
	6.6 Approaches to Discover Modulators of PPIs
		6.6.1 High-Throughput Screening
			6.6.1.1 Chemical Libraries for HTS
				Biology-Oriented Synthesis (BIOS)-Inspired Compound Library
				Multicomponent Reaction (MCR)-Inspired Compound Library
				Diversity-Oriented Synthesis (DOS)-Derived Compound Library
				Cascade Reactions-Derived Compound Library
			6.6.1.2 Assays for HTS of PPI Inhibitors
				Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET)
				Fluorescence Polarization
				Amplified Luminescent Proximity Homogeneous Assay (ALPHA) Screen
				Validation and Structural Optimization of Hits
		6.6.2 Fragment-Based Approach
			6.6.2.1 Identification of Fragment Hits
				Nontethering Methods
				Tethering Methods
			6.6.2.2 Designing Fragments for Tethering
				Tethering with Breakaway Extenders
				Tethering with Extenders Used as a Fragment Assembly Tool
		6.6.3 Structure-Based Approach
			6.6.3.1 Anchor-Based Approach
				Anchor-Based Designing of Inhibitors Against p53-MDM2 Interaction
				Anchor-Based De Novo Designing of Inhibitors Against VHL/HIF1α Interaction
				Anchor-Based Bioisostere Replacement-Dependent Designing of Inhibitors Against β-Catenin-TCF Interaction
			6.6.3.2 Designing of Inhibitors Based on Secondary Structures Involved in PPI
				Small-Molecule Library of Secondary Structure Mimetics
				Computational Designing of α-Helix Mimetics Against p53-MDM2 and p300-HIF1α
				Rational Designing of α-Helix Mimetics Against c-Myc/Max
	6.7 Virtual Screening
		6.7.1 Ligand-Based Virtual Screening (LBVS)
			6.7.1.1 QSAR Modeling
			6.7.1.2 Similarity Methods
			6.7.1.3 Pharmacophore-Based Modeling
		6.7.2 Structure-Based Virtual Screening (SBVS)
			6.7.2.1 Molecular Docking
			6.7.2.2 Binding Site Comparisons
			6.7.2.3 Pharmacophore-Based Models
		6.7.3 Integrated SBVS and LBVS
			6.7.3.1 Sequential Combination of SBVS and LBVS
			6.7.3.2 Parallel Combination of SBVS and LBVS
		6.7.4 Hybrid Combination of SBVS and LBVS
			6.7.4.1 Interaction-Based Hybrid Methods
			6.7.4.2 Similarity Docking-Based Hybrid Methods
				Predicting the Pose of Ligands
				Similarity Guide Scoring Scheme
	6.8 Challenges in PPI-Based Drug Discovery
	6.9 Conclusions
	References
7: Small-Molecule Inhibitors of Protein-Protein Interactions as Therapeutics
	7.1 Introduction
	7.2 Targeting p53/MDM2 Interaction
		7.2.1 Natural Products as Inhibitors of p53/MDM2
		7.2.2 β-Hairpin and α-Helix Peptidomimetics
		7.2.3 Terphenyl
		7.2.4 Nutlins
		7.2.5 Benzodiazepines
		7.2.6 Spirooxindoles
		7.2.7 Chromenotriazolopyrimidines
		7.2.8 Piperidinones
			7.2.8.1 Indolo-Imidazoles
	7.3 Modulation of PPIs Associated with Hsp90 Protein
		7.3.1 Inhibitors Targeting N-Terminal ATP-Binding Site of Hsp90
			7.3.1.1 Radicicol
			7.3.1.2 Purine Scaffolds
			7.3.1.3 Resorcyclic Pyrazole/Isoxazole Series
		7.3.2 Inhibitors Targeting Hsp90
		7.3.3 Inhibitors Targeting Interactions of Hsp90/Co-Chaperone
			7.3.3.1 Targeting the Cdc37/Hsp90 Interaction
			7.3.3.2 Inhibiting the TPR Co-Chaperones/Hsp90 Interaction
	7.4 Inhibitors Targeting β-Catenin/T-Cell Factor PPIs
		7.4.1 Inhibitors Designed Against β-Catenin/Tcf4
	7.5 Inhibitors Targeting Bcl-2 Family Proteins
		7.5.1 Peptides and Peptidomimetics Targeting Bcl-2 Family Proteins
		7.5.2 SAHBs (Stabilized α-Helix of BCL-2 Domains)
		7.5.3 Terphenyl
		7.5.4 Natural Products and Their Derivatives
			7.5.4.1 Antimycin A3
			7.5.4.2 Chelerythrine
			7.5.4.3 Polyphenolic Compounds
			7.5.4.4 TW-37
			7.5.4.5 Epigallocatechin-3-Gallate (EGCG)
		7.5.5 Synthetic Molecules
			7.5.5.1 H14
			7.5.5.2 BH3Is
			7.5.5.3 YC137
			7.5.5.4 ABT-737
	7.6 Inhibitors Targeting 14-3-3 PPIs
		7.6.1 R18
		7.6.2 Exos Macrocyclic Peptide
		7.6.3 Tau Epitope
		7.6.4 BV01, BV02, BV101
		7.6.5 Fobisin
	7.7 Inhibitors Targeting c-Myc/Max Interactions
	7.8 Inhibitors of KRAS and PDE δ Interactions
	7.9 Inhibitors of CD40 and CD40L Interactions
	7.10 Inhibitors of Skp2/Skp1 Interactions
	7.11 Inhibitors of Keap1/Nrf2 Interactions
	7.12 Inhibitors of PD1/PD-L1 Interactions
	7.13 Inhibitors Against GTPases
		7.13.1 Small Inhibitors Against Ras
		7.13.2 Peptide-Based Ras Inhibitors
		7.13.3 Inhibitors for RasGEF (SOS1)
	7.14 Conclusion
	References