Subject Index

2-dimensional combinatorial screening (2DCS), 56

3,5-dimethylisoxazole, 106

4,5-dihydrobenzodiazepinone (THBD)-based ligand, 99

4-chloro-3-sulfamoylbenzoic acid (Cl-SABA) derivative, 78

5-azidopentanoic acid, 42

A549 cells, 71

ABPP. See activity-based protein profiling (ABPP)

activity-based protein profiling (ABPP), 123

affinity-based DEL selections, 1

• nucleic acid targets, 11

  • DNA targets, 12

  • RNA targets, 12–13

• protein targets, 6

  • DNA- and RNA-binding proteins, 10–11

  • enzyme ligands with specific mechanisms of action (MOAs), 7–8

  • G protein-coupled receptors (GPCRs), 9–10

  • protein–protein interaction (PPI) targets, 8–9

• strategies, 2

  • bead-based DELs, DEL selection with, 6

  • capillary electrophoresis (CE)- and liquid chromatography (LC)-based selection strategies, 5

  • cell-based DEL selections, 5–6

  • solid support, DEL selections on, 2

  • solution-based DEL selection strategies, 2–5

affinity selection mass spectrometry (ASMS), 18

agonist-specific selection, covalent crosslinking with split protein reconstitution for, 73–75

AI/ML models, 18–19, 32

Amgen, 1

AMR. See antimicrobial resistance (AMR)

angiotensin II type I receptor (AT1R), 10

antibacterial discovery via phenotypic DEL screening, 55

antimicrobial resistance (AMR), 94

ASMS. See affinity selection mass spectrometry (ASMS)

AT1R. See angiotensin II type I receptor (AT1R)

ATX. See autotaxin (ATX)

autotaxin (ATX), 48

AZ6343, 9

Bacillus subtilis, 94

BBs. See building blocks (BBs)

bead-based DELs, 6

bead-specific barcoding (BSB) informatics, 50

benzimidazoles, 56

bifunctional degraders, 135

binder trap enrichment (BTE)

• direct injection into xenopus oocyte followed by, 81–83

• strategy, 2

BioID tag, 73

bivalent DEL binding to multivalent protein target, 77–78

Bruton’s tyrosine kinase (BTK) inhibitor, 8, 119

BSB informatics. See bead-specific barcoding (BSB) informatics

BTE strategy. See binder trap enrichment (BTE) strategy

BTK inhibitor. See Bruton’s tyrosine kinase (BTK) inhibitor

building blocks (BBs), 127

CA-12. See carbonic anhydrase 12 (CA-12)

CAIX. See carbonic anhydrase IX (CAIX)

CAPA. See chloroalkane penetration assay (CAPA)

capillary electrophoresis (CE)-based selection strategies, 5

carbonic anhydrase 12 (CA-12), 71

carbonic anhydrase IX (CAIX), 77

carboxylic acid beads, 6

cathepsin D activity, 46

CBX proteins. See chromobox (CBX) proteins

CD25, 9

CD44, 76

CE-based selection strategies. See capillary electrophoresis (CE)-based selection strategies

cell-based DEL selections, 5–6

cell-based screening, 54

cell exterior, direct equilibrium binding to, 65–70

cell penetration by cell penetrating peptide followed by covalent crosslinking to protein target, 78–81

chemical inducers of proximity (CIPs), 94

chloroalkane penetration assay (CAPA), 78

chromobox (CBX) proteins, 107

“CIP-DEL” (Chemical Inducer of Proximity), 141

CIPs. See chemical inducers of proximity (CIPs)

Cl-SABA derivative. See 4-chloro-3-sulfamoylbenzoic acid (Cl-SABA) derivative

CNBr. See cyanogen bromide (CNBr)

copper-catalyzed azide–alkyne cycloaddition (CuAAC), 42, 57, 127

covalent crosslinking

• to protein target, 70–73

• with split protein reconstitution for agonist-specific selection, 73–75

covalent DNA-encoded library (CoDEL), 119

• future perspectives, 130–131

• hits selected from, 122–124

• synthesis, 129–130

• warheads and on-DNA chemistry in CoDELs

  • potential warheads and on-DNA chemistry in CoDELs, 126–129

  • reported warheads targeting cysteine residues and on-DNA chemistry, 124–126

  • reported warheads targeting non-cysteine residues and on-DNA chemistry, 126

covalent inhibitors

• different discovery methods of, 120–121

• in pharmacy, 119–120

covalent selection methods, 129

CT26.3E10 cells, 77

CuAAC. See copper-catalyzed azide–alkyne cycloaddition (CuAAC)

cyanogen bromide (CNBr), 6

CysLT. See cysteinyl-leukotriene receptor (CysLT)

cysteinyl-leukotriene receptor (CysLT), 10

data processing and modeling considerations in DEL-ML, 22

DCAF1. See DDB1-CUL4-associated factor (DCAF1)

DDB1-CUL4-associated factor (DCAF1), 139

DDR1 kinase. See discoidin domain receptor 1 (DDR1) kinase

DEDL. See DNA-encoded dynamic library (DEDL)

deep learning, 19

degraders and glues, DEL screening for, 141–145

DEL-ML. See DNA-encoded library machine learning (DEL-ML)

delta opioid receptor (DOR), 70

design–make–test–analyze (DMTA) cycles, 33

differential scanning fluorimetry (DSF), 139

direct equilibrium binding to cell exterior, 65–70

discoidin domain receptor 1 (DDR1) kinase, 48

DMTA cycles. See design–make–test–analyze (DMTA) cycles

Dmt-Tic-Lys (DTK), 70

DNA- and RNA-binding proteins, 10–11

DNA-encoded dynamic library (DEDL), 5

DNA-encoded library machine learning (DEL-ML), 17

• applications of, in the literature, 31–32

• challenges for, 32–33

• data processing and modeling considerations in, 22

• DEL-data complexity, 25–27

• field, 33–37

• models, application of, 29–31

• molecular representation, 24–25

• preparation of data for input, 22–24

DNA targets in DEL selection, 12

DOR. See delta opioid receptor (DOR)

dose-response activity-based OBOC-DEL screening, 52–54

dose-response screening, 52

DSF. See differential scanning fluorimetry (DSF)

DTK. See Dmt-Tic-Lys (DTK)

E3 ligase ligand discovery and targeted protein degradation, application of DELs for, 134

• degraders and glues, DEL screening for, 141–145

• perspectives, 145–148

• targeted protein degradation (TPD)

  • DELs for the discovery of TPD compounds, 136–138

  • DELs for the identification of target binders for, 140–141

• targeted protein degradation, 134–136

E3 ubiquitin ligase binders, DELs for the identification of, 138–140

EDVP complex. See EED-DDB1-VPRBp (EDVP) complex

EED-DDB1-VPRBp (EDVP) complex, 139

EGFR inhibitor. See epidermal growth factor receptor (EGFR) inhibitor

encoded self-assembling compound libraries (ESAC), 99, 102

endogenous protein targets via label transfer of ssDNA tag, 75–76

endothelin receptor A (ETAR), 10

enzyme ligands with specific mechanisms of action, 7–8

enzymic fusion protein tag, proximity-labeling with, 73

epidermal growth factor receptor (EGFR) inhibitor, 76, 119

ERα binders. See estrogen receptor α (ERα) binders

ESAC. See encoded self-assembling compound libraries (ESAC)

estrogen receptor α (ERα) binders, 140

ETAR. See endothelin receptor A (ETAR)

Expi293F cells, 10

FACS. See fluorescence-activated cell sorting (FACS)

FADS component. See fluorescence-activated droplet sorting (FADS) component

false discovery rate (FDR), 50

FBDD. See fragment-based drug discovery (FBDD)

FDR. See false discovery rate (FDR)

fluorescence-activated cell sorting (FACS), 6, 54

fluorescence-activated droplet sorting (FADS) component, 46

folate receptor (FR) system, 75, 76

fragment-based drug discovery (FBDD), 97

Frenz-type delay lines, 46

FR system. See folate receptor (FR) system

GCNNs. See graph convolutional neural networks (GCNNs)

GID4. See glucose-induced degradation protein 4 homolog (GID4)

GIZ. See growth inhibition zone (GIZ)

GlaxoSmithKline (GSK), 1

glucose-induced degradation protein 4 homolog (GID4), 138

GPCRs. See G-protein coupled receptors (GPCRs)

G-protein-biased agonist of K-opioid receptor, 10

G-protein coupled receptors (GPCRs), 9–10, 65

graph convolutional neural networks (GCNNs), 19

growth inhibition zone (GIZ), 94

GSK. See GlaxoSmithKline (GSK)

HDNA. See headpiece DNA (HDNA)

headpiece DNA (HDNA), 42

HEK293 cells, 9, 65, 79

HEK293T cells, 70

high-performance liquid chromatography (HPLC) apparatus, 10

high-throughput screening (HTS), 18, 43, 136, 141

HitGen approach, 1, 143

HIV-1 protease, 104

HMLEs. See human mammary epithelial cells (HMLEs)

HPLC apparatus. See high-performance liquid chromatography (HPLC) apparatus

HTS. See high-throughput screening (HTS)

human mammary epithelial cells (HMLEs), 78

ibrutinib, 119

ICAM-1. See intercellular adhesion molecule 1 (ICAM-1)

IDPCR. See interaction dependent PCR (IDPCR)

IDPs. See intrinsically disordered proteins (IDPs)

IDUP method. See Interaction Determination Using Unpurified Proteins (IDUP) method

IgG. See immunoglobulin G (IgG)

IL2. See interleukin-2 (IL2)

IMiDs. See immunomodulatory drugs (IMiDs)

immunoglobulin G (IgG), 54

immunomodulatory drugs (IMiDs), 135

integrated assay incubation, 46

interaction dependent PCR (IDPCR), 5

Interaction Determination Using Unpurified Proteins (IDUP) method, 122

intercellular adhesion molecule 1 (ICAM-1), 8

interleukin-2 (IL2), 8–9

internet of things (IoT), 17

intrinsically disordered proteins (IDPs), 13

IoT. See internet of things (IoT)

isothermal titration calorimetry (ITC), 138

ITC. See isothermal titration calorimetry (ITC)

JAK3. See Janus kinase 3 (JAK3)

Janus kinase 3 (JAK3), 8

K-opioid receptor, G-protein-biased agonist of, 10

LBD. See ligand binding domain (LBD)

LC-based selection strategies. See liquid chromatography (LC)-based selection strategies

LFA-1. See lymphocyte function-associated antigen 1 (LFA-1)

ligand binding domain (LBD), 11

ligand observed NMR (LO-NMR), 99

liquid chromatography (LC)-based selection strategies, 5

live cell-mediated DEL affinity selection

• for cell surface proteins, 64

  • bivalent DEL binding to a multivalent protein target, 77–78

  • covalent crosslinking to the protein target, 70–73

  • covalent crosslinking with split protein reconstitution for an agonist-specific selection, 73–75

  • direct equilibrium binding to the cell exterior, 65–70

  • endogenous protein targets via label transfer of an ssDNA tag, 75–76

  • proximity-labeling with an enzymic fusion protein tag, 73

• for targets within cells

  • cell penetration by cell penetrating peptide followed by covalent crosslinking to protein target, 78–81

  • direct injection into xenopus oocyte followed by binder trap enrichment, 81–83

LO-NMR. See ligand observed NMR (LO-NMR)

lymphocyte function-associated antigen 1 (LFA-1), 8

lysine, 128

machine learning (ML), 14, 17–22, 27–29, 84, 111. See also DNA-encoded library machine learning (DEL-ML)

MBH reaction. See Morita–Baylis–Hillman (MBH) reaction

MCF7 cells, 72

MDR pathogens. See multidrug-resistant (MDR) pathogens

mechanism of action (MOA), 7

• enzyme ligands with specific MOAs, 7–8

Merck (MSD), 1

MGDs. See molecular glue degraders (MGDs)

ML. See machine learning (ML)

MOA. See mechanism of action (MOA)

molecular glue degraders (MGDs), 135

molecular representation, 24–25

monomeric RNase L, 11

Morita–Baylis–Hillman (MBH) reaction, 130

MPO-oriented predictions. See multi-parameter optimization (MPO)-oriented predictions

multidrug-resistant (MDR) pathogens, 92

multi-parameter optimization (MPO)-oriented predictions, 21

multivalent protein target, bivalent DEL binding to, 77–78

NADEL, 89

NAMs. See negative allosteric modulators (NAMs)

Na-terminal acetyltransferase, 8

negative allosteric modulators (NAMs), 10

next generation sequencing (NGS), 1

NGS. See next generation sequencing (NGS)

nucleic acid targets in DEL selection, 11

• DNA targets, 12

• RNA targets, 12–13

NUDEL technology, 106

OBOC-DEL screening. See one-bead-one-compound DEL (OBOC-DEL) screening

o-NBA. See o-nitrobenzyl alcohol (o-NBA)

on-bead affinity-based screening, 54–56

on-DNA chemistry in CoDELs

• potential warheads and, 126–129

• reported warheads targeting cysteine residues and, 124–126

• reported warheads targeting non-cysteine residues and, 126

on-DNA medicinal chemistry, 87

• focused libraries, 89–97

• fragments and fragment expansion, 97–106

• future directions, 109–111

• hit optimisation, 106–109

one-bead-one-compound DEL (OBOC-DEL) screening, 6, 41, 42, 144

• examples, 52

  • cell-based screening, 54

  • dose-response activity-based OBOC-DEL screening, 52–54

  • on-bead affinity-based screening, 54–56

  • pharmacokinetic DEL screening, 56–58

• microfluidic, 43–47

• statistics, 48–52

o-nitrobenzyl alcohol (o-NBA), 128–129

osimertinib, 119

PAMPA. See parallel artificial membrane permeability assay (PAMPA)

PAMs. See positive allosteric modulators (PAMs)

PAR2 ligands. See protease-activated receptor 2 (PAR2) ligands

parallel artificial membrane permeability assay (PAMPA), 57

PC-linker. See photocleavable linkers (PC-linker)

PCR. See polymerase chain reaction (PCR)

peptidyl-prolyl cis/trans isomerase NIMA-interacting-1 (Pin1), 8

permeation-based OBOC-DEL screening, 57

Pfizer, 1

pharmacokinetic DEL screening, 56–58

phenotypic DEL screening, antibacterial discovery via, 55

photocleavable linkers (PC-linker), 42

POI. See protein of interest (POI)

polymerase chain reaction (PCR), 25

positive allosteric modulators (PAMs), 10

post-translational modifications (PTMs), 7

PPI targets. See protein–protein interaction (PPI) targets

PR-AUC metrics. See precision-recall area under the curve (PR-AUC) metrics

precision-recall area under the curve (PR-AUC) metrics, 28

property-focused DEL, 93

PROTACs. See proteolysis-targeting chimeras (PROTACs)

protease-activated receptor 2 (PAR2) ligands, 9

protein of interest (POI), 134

protein–protein interaction (PPI) targets, 8–9

protein target

• covalent crosslinking to, 70–73

• in DEL selections, 6

  • DNA- and RNA-binding proteins, 10–11

  • enzyme ligands with specific mechanisms of action (MOAs), 7–8

  • G protein-coupled receptors (GPCRs), 9–10

  • protein–protein interaction (PPI) targets, 8–9

protein targets, assays of DNA-encoded libraries against, 63

• live cell-mediated DEL affinity selection for cell surface proteins, 64

  • bivalent DEL binding to multivalent protein target, 77–78

  • covalent crosslinking to the protein target, 70–73

  • covalent crosslinking with split protein reconstitution for agonist-specific selection, 73–75

  • direct equilibrium binding to the cell exterior, 65–70

  • endogenous protein targets via label transfer of ssDNA tag, 75–76

  • proximity-labeling with enzymic fusion protein tag, 73

• live cell-mediated DEL affinity selection for targets within cells

  • cell penetration by cell penetrating peptide followed by covalent crosslinking to protein target, 78–81

  • direct injection into xenopus oocyte followed by binder trap enrichment, 81–83

• perspective, 83–84

proteolysis-targeting chimeras (PROTACs), 94, 134, 145

proximity-labeling with enzymic fusion protein tag, 73

PTMs. See post-translational modifications (PTMs)

QC. See quality control (QC)

qHTS. See “quantitative HTS” (qHTS)

QSAR analysis. See quantitative structure–activity relationship (QSAR) analysis

quality control (QC), 42

“quantitative HTS” (qHTS), 52

quantitative structure–activity relationship (QSAR) analysis, 17

RAC approach. See receptor-affinity chromatography (RAC) approach

receiver operator characteristic area-under the curve (ROC-AUC), 28

receptor-affinity chromatography (RAC) approach, 10

receptor interacting protein kinase 2 (RIPK2) degrader, 141

recombinant proteins, 7

RIPK2 degrader. See receptor interacting protein kinase 2 (RIPK2) degrader

ritlecitinib, 8

RNA-binding proteins, 10–11

RNA targets in DEL selection, 12–13

ROC-AUC. See receiver operator characteristic area-under the curve (ROC-AUC)

Roche, 1

SAR. See structure–activity relationship (SAR)

SBDD. See structure based drug design (SBDD)

solid-phase DEL design, 42–43

solid-phase DNA-encoded library technology, 41

• assay development, 47–48

• future directions, 58

• microfluidic OBOC-DEL screening, 43–47

• one-bead-one-compound DEL (OBOC-DEL) sampling and screening statistics, 48–52

• one-bead-one-compound DEL (OBOC-DEL) screening examples, 52

  • cell-based screening, 54

  • dose-response activity-based OBOC-DEL screening, 52–54

  • on-bead affinity-based screening, 54–56

  • pharmacokinetic DEL screening, 56–58

solid support, DEL selections on, 2

solution-based DEL selection strategies, 2–5

split protein reconstitution, covalent crosslinking with, for agonist-specific selection, 73–75

SPR. See surface plasmon resonance (SPR)

ssDNA tag, endogenous protein targets via label transfer of, 75–76

structure–activity relationship (SAR), 31, 141

structure based drug design (SBDD), 20

“suicide” inhibitors, 120

surface plasmon resonance (SPR), 139

Suzuki–Miyaura coupling, 105

tandem ubiquitin binding entities (TUBEs), 145

Tanimoto distance-based splitting, 28

targeted protein degradation (TPD), 134, 148

• DELs for the discovery of TPD compounds, 136–138

• DELs for the identification of target binders for, 140–141

targeted protein degradation, 134–136

T-DEL. See trio-pharmacophore DEL (T-DEL)

THBD-based ligand. See 4,5-dihydrobenzodiazepinone (THBD)-based ligand

TPD. See targeted protein degradation (TPD)

transferrin receptor 1, 76

trio-pharmacophore DEL (T-DEL), 102–103

TUBEs. See tandem ubiquitin binding entities (TUBEs)

ubiquitin proteosome system (UPS), 134

UPS. See ubiquitin proteosome system (UPS)

VAEs. See variational auto-encoders (VAEs)

variational auto-encoders (VAEs), 24

Vepdegestrant, 140

VHL-based STAT3 degrader. See von Hippel–Lindau (VHL)-based STAT3 degrader

von Hippel–Lindau (VHL)-based STAT3 degrader, 135

Vpr, 139

Vpx, 139

warheads and on-DNA chemistry in CoDELs

• potential, 126–129

• reported warheads targeting cysteine residues and on-DNA chemistry, 124–126

• reported warheads targeting non-cysteine residues and on-DNA chemistry, 126

WuXi AppTec, 1, 122

X-Chem, 1

Xenopus laevis oocytes, 81, 83

xenopus oocyte, direct injection into

• followed by binder trap enrichment, 81–83