Download Protein Function

첨단화학의 이해
Synthesis
Make me a molecule
Chemistry
Biology
Materials
첨단화학의 이해
DNA, Genes, and Proteins
첨단화학의 이해
Genomics, Proteomics and Chemical Genetics
Genomics
Control
Biological
Functions
Gene Sequence:
- ~30,000 genes
- unable to identify therapeutic
targets
- no protein function and
Proteomics
disease relevance
Drug
Discovery
Chemical
Genetics
Protein Function:
Small Molecules:
- purification and structure
- modulate biological
determination
functions of proteins
- ~100,000 proteins in human
- 75% no known cellular functions
첨단화학의 이해
Protein Function (Drug Action)
protein
false
signal
deactivate
protein function
normal
signal
activate
protein function
첨단화학의 이해
Selected Medications of 20th Century
CO 2Et
N
O
O
N
HN
O
NH 2
O
F
N
N
O
N
HO
S
N
N
H
Cl
N
O
NH
O
H
OH
Cl
H
N
Paxil
Cl
Claritin
(antihistamine,
i.e. antiallergic)
Viagra
N
H
Viracept
(treatment of AIDS)
(treatment of impotence)
Zoloft
(psychotherapeutic)
(psychotherapeutic)
H2 N
O
N
H
N
S
HO 2C
H
N
HS
NO 2
Zantac
(treatment of ulcer)
N
N
H2N
N
N
N
O
Captopril
(treatment of hypertension)
H
N
NH 2
O
S
MeO
(local anesthetic)
O
O
N
N
OMe
Prilosec
(antispasmodic)
Carboplatin
(treatment of ovarian cancer)
N
NMe 2
Novocain
Prozac
(antidepressant)
O
HO
O
Acyclovir
(antiviral)
Pt
HN
NH
O
O
O
O
F3C
NH 2
N
H
H
N
CN
N
H
S
Tagamet
(treatment of ulcer)
N
O
N
Cl
N
Valium
(tranquilizer)
첨단화학의 이해
Selected Medications of 20th Century
OH
H
H
OH
OH
H
HO
O
H
N
O
H
R
H
H
HO
H
H
O
O
O
O
RO
norethindrone
17-ethynylstradiol
R= H Mevacor
R=Me Zocor
(treatment of high cholesterol)
(the "Pill"; contraceptive)
R= H Morphine
R= Me Cocaine
(pain killer)
O
HO
OMe
HO
OH
O
CO 2H
O
O
N
N
HO
O
O
Clarithromycin
(antibacterial)
O
N
S
NH 2
OH
H H
H
Clavulanic acid
(-lactamase inhibitor)
Ampicillin
(antibiotic)
OMe
CO 2H
O
OH
Augmentin
(antibiotic)
첨단화학의 이해
Target-Oriented Organic Synthesis
Known active sites
of target proteins
Design and synthesis
of target molecules
biological effects
첨단화학의 이해
Diversity-Oriented Organic Synthesis
unknown proteins
이상
Library of diverse
small molecules
정상
첨단화학의 이해
Combinatorial Chemistry
첨단화학의 이해
Combinatorial Library
•
•
•
•
4 개의 monomer
Nn Combinations
44 = 256개
tetramer
첨단화학의 이해
Solid Phase Synthesis의 기본원리
resin +
monomer
shake
wash
wash
resin
cleavage
첨단화학의 이해
Solid-Phase Synthesis of Peptides
In 1960s, Bruce Merrifield: peptide synthesis from amino acids
polymer
bead
amino acid
cleave
peptide
첨단화학의 이해
Solid Phase Library Synthesis
• polymer supported synthesis: easy purification
• fast generation of diverse library of molecules in few steps
• limited reactions compared to solution reactions
Split-Mix (split-pool) synthesis
 Parallel synthesis
첨단화학의 이해
tag each bead!
Split-Mix Process
Mix-Split
Couple
Mix-Split
Couple
33= 27
첨단화학의 이해
Parallel synthesis
- no tagging beads!
- synthesis of small number of focused library
첨단화학의 이해
Solid Phase Library
In 1991s, Houghten & Lam: synthesis of a huge peptide library
20 amino acids
Solid-phase synthesis
202 = 400 dipeptides
DNA: fully automatic (solution)
peptide
203 = 8000 tripeptides
carbohydrate
204 = 160,000 tetrapeptides
small molecule (drug-like)
ln 1992, Jon Ellman: synthesis of non-peptide drug-like molecules by
solid phase synthesis
첨단화학의 이해
Combination of Chemical Building Blocks
2,180,106 compounds
첨단화학의 이해
Virtual Library
virtual library: computer simulated fitting of virtual molecules with the
active site of the target enzyme
Novel compounds that bind to enzymes
or receptors can be discovered by finding
two fragments that bind and then
synthetically combining
첨단화학의 이해
Applications of Combinatorial Chemistry
Chemical biology: diversity-oriented synthesis of small organic
molecules
Pharmaceutical industry: rapid synthesis of a huge number of drug-like
molecules
Material science: new approach for the discovery of new materials
Catalyst discovery: fast discovery of new catalysts
첨단화학의 이해
Supramolecular Chemistry
첨단화학의 이해
1. Molecular chemistry- Covalent bond
O
H 2N
NH 2
urea
150 years ago
palytoxin
첨단화학의 이해
초분자 화학
2. Supramolecular chemistry- Chemistry beyond molecules
Assembly of molecules – Molecular recognition
Non-covalent bonds:
- electrostatic forces
- hydrogen bonds
- van der Waals interactions
- dipole interactions
- hydrophobic interactions, etc
1987 노벨화학상: 초분자화학
Charles Pedersen, Jean-Marie Lehn, and Donald J. Cram
첨단화학의 이해
DNA and Hydrogen Bonds
O
NH2
N
H
N
N
R
adenine
N
O
R
thymine
NH2
O
N
N
R
N
N
H
N
O
N
R
cytosine
NH2
guanine
O P O
O
O
O
Base
첨단화학의 이해
DNA and Hydrogen Bonds
O
N
N
R
N
N
O
H
N
R
R
O
N H
N
N
N H
N
H
H
H N
H N
N
N
N
H
O
N
R
H
H
Which pair forms stronger hydrogen bonds? And Why?
-
+
+
-
+
-
-
+
+
-
+
-
첨단화학의 이해
DNA and Hydrogen Bonds
+
+
+
+
-
3.9x108 M-1
+
+
+
-
+
+
+
+
3.6x106 M-1
+
-
3.3x104 M-1
+
+
+
+
-
+
+
-
3.3x104 M-1
3.6x106 M-1
R
R
O
H
O
N
2
N
H
N
H
N
+
+
O
N
H
O
H
N
N
H
N
N
R
N
O
H
N
H
N
H
O
+
+
-
+
+
3.1x102M-1
첨단화학의 이해
New Materials Based on Hydrogen Bonds
R
R
H
N
O
N
O
N
H
O
N
H
N
H
H
N
N
H
N
O
R
O
H
N
N
N
H
H
N
O
O
N
H
H
N
N
H
O
H
N
H
N
R
R
O
N
N
N
H
O
O
N
H
H
N
N
H
N
R
R
O
O
H
N
N
N
H
H
N
O
O
H
N
H
N
H
O
N
N
R
n
N
R
N
O
H
N
H
N
H
O
첨단화학의 이해
Crown Ethers
O
O
K+
O
O
O
O
O
O
Na+
O
O
O
18-crown-6
Cryptand
Crown ether
O
O
O
O
O
- 11 kcal/ mol
O
O H
N
K+
N
CH3
N
O
O
O
O
K+
O
15-crown-5
O
- 18 kcal/ mol
H3C
N
O
H
N+
R
N
H
CH3
O
첨단화학의 이해
Preorganized Ionophores
Preorganization: both binding affinity and selectivity are
considerably increased
O
O
H
O
H
O
H H
O
O
O
+
K
O
O
K+
O
O
O
O
O
O
O
O
OMe
O
O
Me
Me
Me
MeO
O
OMe
O
W.C. Still
D.J. Cram
첨단화학의 이해
Anion Recognition
첨단화학의 이해
Anion Recognition
첨단화학의 이해
Chemosensors
Signals:
- fluorescence
- color
- electric signal...
첨단화학의 이해
Chemosensors
O
N
H3C
S
NH
NH
CH3
H
N
O
Hg(OAc)2
N N
CH3
H3C
H2O-MeOH
(4 : 1)
N
H
O
N
H
N
H
O
Hg(ClO4)2, CH3CN
(98%)
1 only Hg2+ Ag+ Cu2+ Cd2+ Pb2+ Zn2+
N
첨단화학의 이해
Carcerand
O
O
+ CO2
첨단화학의 이해
Molecular Machine
첨단화학의 이해
생체 분자기계
Linear movement - muscle
(myosin moving along an actin filament)
ATP Synthase
Bacterial Flagellar Motor
첨단화학의 이해
Interlocked Molecules
Rotaxane
Rota (wheel) + axis (axle)
Catenane
Catena (chain)
첨단화학의 이해
분자 셔틀 버스 이동
첨단화학의 이해
인공 분자기계
A catenane-based switching
device for electric circuits.
첨단화학의 이해
인공 분자기계
Catenane-based molecular rotor. A unidirectional rotation of the small
rings along the large ring is achieved by their sequential complexation
and decomplexation with four station parts A-D on exposure to light,
heat, and chemical stimuli.
첨단화학의 이해
분자 근육
첨단화학의 이해
분자 엘리베이터
첨단화학의 이해
분자 가위
첨단화학의 이해
인공 분자기계
Chiral molecular motor composed of a tetrasubstituted alkene.
Photoinduced and thermal-induced unidirectional rotation.