Chemical biology — the application of chemical tools to biological systems; distinct from biochemistry (which studies the chemistry of life as-is). Foundations: (1) Bioorthogonal chemistry (Bertozzi 2022 Nobel) — reactions with…
chemical-biology
Bioorthogonal chemistry: k₂ > 1 M⁻¹s⁻¹, zero biological cross-reactivity
Bioorthogonal chemistry (Bertozzi 2022 Nobel) — reactions that operate in living-cell / whole-organism conditions with two simultaneous…
Activity-based probe: warhead + linker + reporter; Langmuir occupancy
Activity-based protein profiling (Cravatt-Wright 2008) — a chemical-biology platform for measuring enzyme engagement in native cellular…
Click chemistry: CuAAC 1,3-dipolar cycloaddition → 1,2,3-triazole
Click chemistry (Sharpless-Meldal-Tornøe 2001 coinage; Sharpless-Meldal-Bertozzi 2022 Nobel) — a modular ligation philosophy defined by…
TCO+tetrazine k₂ vs SPAAC: 10⁶ / 10⁻¹ = 10⁷ (7 orders)
Sympy-exact witness of the bioorthogonal rate-ratio identity. Setup: k_TCO = 10⁶ M⁻¹ s⁻¹ (Blackman-Royzen-Fox 2008), k_SPAAC = 10⁻¹ M⁻¹…
ABP Langmuir: θ=L/(K_d+L); θ(K_d)=1/2, θ(∞)=1, θ(0)=0
Sympy-exact witness of the Langmuir hyperbolic occupancy law applied to activity-based probe binding. Setup: θ(L) = L/(K_d + L) on…
Click regio-count: thermal Huisgen 2 / CuAAC 1 ⇒ ratio 2
Sympy-exact witness of the CuAAC-vs-Huisgen regio-selectivity count. Setup: thermal Huisgen 1,3-dipolar cycloaddition of azide +…
PROTAC ternary-complex cooperativity framework: α = K_d^binary / K_d^ternary (E3-target-degrader design metric)
PROTAC (proteolysis-targeting chimera) ternary-complex cooperativity: a bifunctional small molecule recruits an E3 ubiquitin ligase to a…
Fluorogenic probe quantum-yield enhancement framework: E = Φ_bound / Φ_free (dark-to-bright turn-on)
Fluorogenic-probe quantum-yield enhancement: conditional fluorophores designed to be quenched in the free state and become emissive on…
Activity-based probe first-order labeling framework: f(t) = 1 − exp(−k_obs·t) with half-life ln(2)/k
Activity-based probe (ABP) first-order irreversible labeling kinetics: a covalent probe reacts with an active-site residue (e.g. Cys, Ser…
PROTAC cooperativity: α = 1 at neutrality; α = 10 at 10-fold positive cooperativity (canonical pins)
Cooperativity evaluations: α = K_d^binary/K_d^ternary at cooperativity-neutral (K_d^binary = K_d^ternary = 1) equals the exact integer 1;…
Fluorogen QY enhancement: E = 1 (no turn-on); E = 100 (HaloTag-class); log₁₀(100) = 2 (two decades)
Enhancement evaluations: E = Φ_bound/Φ_free equals exact integer 1 in the no-enhancement baseline (Φ_bound = Φ_free); equals exact integer…
ABP labeling efficiency: f(0) = 0; f(ln(2)/k) = 1/2; f(∞) = 1 (three exact saturation witnesses)
Labeling-fraction evaluations: f(t=0) = 0 exactly (no reaction at start); f(t = ln(2)/k) = 1/2 exactly (half-labelled at one half-life);…
Click chemistry (Sharpless-Meldal-Bertozzi)
Sharpless-Meldal 2001 + Bertozzi 2003 bioorthogonal: Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition; Bertozzi strain-promoted…
Activity-based protein profiling (ABPP)
Cravatt 1999 ABPP: serine/cysteine-hydrolase active-site directed reactive probes; chemoproteomic readout via MS/MS; basis of target ID +…
PROTAC degraders (Crews 2001)
Crews 2001 + Arvinas 2013 PROTAC: bivalent ligand recruits E3-ligase to target -> ubiquitin -> proteasome; ARV-471 estrogen-receptor…
Genetic-code expansion (Schultz 2001)
Schultz 2001 amber-suppression with engineered tRNA/synthetase pair; 200+ unnatural amino-acids site-specifically incorporated; basis of…
Split-protein bioluminescence (NanoBiT)
Dixon 2016 NanoBiT split-NanoLuc: large-BiT + small-BiT subunit complementation; Kd reporter for protein-protein interaction in live-cell;…
CRISPR base editing (Liu 2016)
Komor-Liu 2016 cytidine-base editor (CBE) C->T; Gaudelli-Liu 2017 adenine-base editor (ABE) A->G; nick + deaminase fusion to dCas9;…
Chemical biology (Schreiber 1991)
S Schreiber 1991 'chemical-biology' field-defining; modern bioactive-natural-product probe + chemical-genetics small-molecule.
ABPP (Cravatt 2000)
B Cravatt 2000 ABPP fluorophosphonate-serine-hydrolase; modern PROTACs + KRAS-G12C covalent-warhead drug-discovery.
Stable-isotope tracing (Schoenheimer 1935)
R Schoenheimer 1935 deuterium-labeling; modern 13C-flux DeBerardinis 2007 + Met-Flow lipidomics 2024.
Bioorthogonal (Bertozzi 2004)
C Bertozzi 2004 (Nobel 2022) Staudinger-azide ligation; modern strain-promoted SPAAC + DOTA + click-chemistry in cells.
Bumphole (Shokat 1998)
K Shokat 1998 analog-sensitive-kinase + ATP-bumphole; modern selective-inhibition + chemical-genetics signal-transduction tool.
Genetic-code expansion (Schultz 1989)
P Schultz 1989 unnatural-amino-acid + tRNA suppressor; modern 100+ ncAA + 4-base-codon + GCE-based therapeutics 2023+.