Patrick: An Introduction

to Medicinal Chemistry 5e
Chapter 1

DRUGS & DRUG TARGETS

AN OVERVIEW

© Oxford University Press, 2013

Contents
1. Cell Structure
2. Cell Membrane
3. Drug targets
4. Intermolecular bonding forces
4.1 Electrostatic or ionic bonds
4.2 Hydrogen bonds
4.3 Van der Waals interactions
4.4 Dipole-dipole interactions
4.5 Ion-dipole interactions
4.6 Induced dipole interactions
5. Desolvation penalties
6. Hydrophobic interactions

© Oxford University Press, 2013

 1. Cell Structure
(link: Cell Structure)

• Human, animal and plant cells are eukaryotic cells

• The nucleus contains the genetic blueprint for life (DNA)

• The fluid contents of the cell are known as the cytoplasm

• Structures within the cell are known as organelles

• Mitochondria are the source of energy production

• Ribosomes are the cell’s protein ‘factories’

• Rough endoplasmic reticulum is the location for protein synthesis

© Oxford University Press, 2013

1. Cell Structure

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 2. Cell Membrane

Note: Membran sel  penting untuk kehidupan sel

• Membungkus sel dan membatasi sel dari lingkungan sehingga
memelihara perbedaan esential antara sitoplasma dan lingkungan
ekstraseluler
• Membungkus organel-organel sel, spt retikulum endoplasma,
badan Golgi, mitokondria, dll; memelihara perbedaan
karakteristiknya dengan sitoplasma.
• Komponennya dapat bertindak sebagai:
 penghasil ATP, yang digunakan untuk transport molekul-
molekul melewatinya
 penghasil dan penghantar sinyal elektris pada sel saraf
 reseptor atau protein penerima sensor sinyal ekstraseluler
© Oxford University Press, 2013
2. Cell Membrane
Plasma membrane

Phospholipid bilayer

Cytoplasm Nucleus

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Struktur umum membran sel terdiri dari:
◘ 2 lapis lemak/lipid (“lipid bilayer”)
Model mozaik
◘ protein . fluida

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2. Cell Membrane
Bagian dan komposisi dari molekul fosfolipid
(fosfatidilkolin)

CH2CH2NMe3
CH2CH2NMe3 O
Polar O Polar
Polar Head O P O
Head O P O
Group Head Group O
Group O
CH2 CH CH2
CH2 CH CH2 O O
O O O O
O O

Hydrophobic Tails

Hydrophobic Tails
Hydrophobic Tails

Perbedaan pada panjang dan tingkat saturasi dari bagian ekor

(hydrokarbon) molekul fosfolipid mempengaruhi fluiditas dari
suatu membran © Oxford University Press, 2013
Komponen lain dalam lapisan lemak (“lipid bilayer”):
• Kolesterol
- memperbesar batas permeabilitas dari “lipid bilayer”
- mengurangi fluiditas dari membran sel
- mencegah rantai hidrokarbon berikatan satu sama lain
dan berkristalisasi
• Glikolipid
penambahan gugus gula pada molekul lipid  berperan
penting dalam interaksi sel dengan lingkungannya, seperti
- melindungi membran terhadap adanya kondisi ekstrem
(misalnya: pH yang rendah dan enzim degradatif)
- merubah konsentrasi ion (terutama Ca 2+ pada plasma
membran
- proses pengenalan sel, yaitu adhesi antar sel

© Oxford University Press, 2013

2. Cell Membrane
Notes:
• The non polar tails interact with each other by van der Waals
interactions and are hidden from the aqueous media (hydrophobic)

• The polar head groups interact with water at the inner and outer
surfaces of the membrane (hidrofilik)

The cell membrane provides a hydrophobic barrier around the cell

(impermeabel terhadap air), preventing the passage of water and
polar molecules

• Proteins are embedded in the cell membrane (ion channels,

receptors, enzymes and transport proteins)

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2. Cell Membrane
Proteins
Exterior
High [Na+]

Phospholipid
Bilayer

Interior
High [K+]

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■ Lapisan “Lipid bilayer” mempunyai permeabilitas yang berbeda
terhadap berbagai macam molekul

Cepat berdifusi melewati “lipid bilayer

Dapat berdifusi, tetapi lambat

Dapat berdifusi, tetapi sangat lambat

Tidak dapat berdifusi  impermeabel

© Oxford University Press, 2013

Perbandingan konsentrasi ion di dalam dan di luar sel

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 SISTEM TRANSPORT PADA MEMBRAN (Link: transport membrane)

• Transport molekul dari dan ke dalam sel melalui

membran bertujuan untuk:
- Memasukkan suatu komponen yang penting
(termasuk obat) ke dalam sel
- Membuang produk limbah metabolisme sel
- Mengatur konsentrasi ion intraseluler

• Protein membran memegang peranan penting dalam

transport molekul pada sel
 15 – 30 % protein pada sel adalah protein transport
© Oxford University Press, 2013
 2 Kelas Utama Protein Transport pada Membran
1. Protein pembawa (“Carrier”) = permeases = transporters
Mengikat molekul yang akan dibawanya kemudian mengalami perubahan
konformasi sehingga akhirnya dapat menmindahkan molekul tsb dari luar sel
ke dalam sel atau sebaliknya.
2. Protein kanal
Membentuk pori/kanal pada lipid bilayer, ketika pori terbuka membiarkan
molekul-molekul (terutama ion-ion) melewatinya dari dan ke dalam sel atau
sebaliknya.
Transport melalui protein kanal lebih cepat dibandingkan dengan
protein “carrier”

1. Protein “carrier 2. Protein kanal

© Oxford University Press, 2013
 SISTEM TRANSPORT PADA MEMBRAN

Transport pada membran yang diperantarai oleh protein membran

bersifat :
♦ pasif,
- karena adanya perbedaan konsentrasi molekul di dalam dan di
luar sel (konsentrasi gradient)
- melewati protein kanal atau protein “carrier”
♦ aktif,
- karena adanya aktifitas “memompa” molekul-molekul yang
mempunyai perbedaan sifat elektrokimia (electrochemical
gradient) oleh protein “carrier”.
- menggunakan energi, seperti ATP

© Oxford University Press, 2013

© Oxford University Press, 2013
Tranport molekul melalui protein kanal
 Protein kanal membentuk pori yang bersifat hidrofilik
 Mentranfer ion  disebut kanal ion, yang selektif terhadap ion tertentu.
 Dapat tertutup dan kemudian terbuka (“gated”).
 Terbukanya kanal ion karena adanya stimulus, yang berupa:
 perubahan tegangan pada membran (Votage-gated channel)
 stress mekanik (mechanically gated channel)
 ikatan dengan ligan (ligand-gated channel),
o karena adanya molekul mediator ekstraseluler, misalnya
neurotansmitter (transmitter-gated channel)
o karena adanya molekul mediator intraseluler, berupa ion (ion-
gated channel) atau nukleotida (nukleotida-gated channel)

© Oxford University Press, 2013

 1. Drug Targets

Why do drugs work?

• Drugs are chemicals

– Interact with the body’s chemicals

• How/where will they interact?

- Binding through intermolecular forces

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WHY BE CONCERNED ABOUT
HOW DRUGS WORK?

AIDS MEMORIZATION OF:

• FDA Approved and Unapproved Uses

• Interactions with Other Drugs

• Adverse Effects and Contraindications

© Oxford University Press, 2013

WHY BE CONCERNED ABOUT
HOW DRUGS WORK?
AIDS EVALUATION OF MEDICAL LITERATURE:

• Better assessment of new modalities for using drugs

• Better assessment of new indications for drugs

• Better assessment of new concerns regarding risk-benefit

© Oxford University Press, 2013

WHY BE CONCERNED ABOUT
HOW DRUGS WORK?
AIDS PATIENT-DOCTOR RELATIONSHIP:

The patient has more respect for and trust in a therapist who
can convey to the patient how the drug is affecting the
patient’s body.

A patient who understands his/her therapy is more inclined

to become an active participant in the management
of the patient’s disease.

© Oxford University Press, 2013

WHY BE CONCERNED ABOUT
HOW DRUGS WORK?

PEACE OF MIND!

Knowledge of how a drug works increases the therapist’s

confidence that the drug is being used appropriately.

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3. Drug targets
Notes
• Drug targets are large molecules - macromolecules
• Drugs are generally much smaller than their targets
• Drugs interact with their targets by binding to binding sites
• Binding sites are typically hydrophobic hollows or clefts on
the surface of macromolecules
• Binding interactions typically involve intermolecular bonds
• Most drugs are in equilibrium between being bound and
unbound to their target
• Functional groups on the drug are involved in binding
interactions and are called binding groups
• Specific regions within the binding site that are involved in
binding interactions are called binding regions
© Oxford University Press, 2013
 3. Drug Targets

Lipids Protein Nucleic acid Carbohydrate

* Receptor
Cell DNA Cell surface
* Enzymes
membrane RNA carbohydrates
lipids * Transport
proteins Antigens and
* Structural recognition
proteins molecules
(tubulin)

© Oxford University Press, 2013

3. Drug targets
Binding
regions

Drug Binding
groups

Intermolecular
bonds

Binding site

Binding Drug
site

Drug

Induced fit
Macromolecular target Macromolecular target

Unbound drug Bound drug

© Oxford University Press, 2013

3. Drug targets
Notes
• Binding interactions usually result in an induced fit where
the binding site changes shape to accommodate the drug

• The induced fit may also alter the overall shape of the drug
target

• Important to the pharmacological effect of the drug

© Oxford University Press, 2013

 HOW DO DRUGS WORK?
(A Basic introduction…..)

Most drugs work by interacting with

endogenous proteins:

• Some drugs antagonize, block or inhibit endogenous proteins

• Some drugs activate endogenous proteins

• A few drugs have unconventional mechanisms of action

© Oxford University Press, 2013

 HOW DO DRUGS WORK?
Theory of Drug Action

 Fischer’s ‘Lock and Key’ Hypothesis

 Every ‘lock’ has its own ‘key’

 If the ‘key’ is not precise, the ‘lock’ does not open
 The ‘drug’ is the key that has to fit the target
specifically and productively
29
© Oxford University Press, 2013
 Theory of Drug Action

 Corollary of ‘Lock & Key’ Hypothesis

O
CH3 OH CH3 CH3 OH
C CH

HO
HO HO

OH
O

HO O O

O
H3C CH3 OH
CH2 N CH3 H2C
CH3
CH2
HO H3C

 Does not explain why some ‘keys’ open doors partially?

…… e.g., partial agonists or antagonists
MEDC 603 Fall 2007 30
© Oxford University Press, 2013
 Theory of Drug Action

 Koshland’s ‘Induced-Fit’ Hypothesis

 At least two steps …… e.g., step 1 is initial binding and step 2

is a change in structure of the receptor (and/or drug)
 Receptor is flexible! …… can wrap around the drug …… the
zipper model is extreme case of induced-fit
 All intermediate cases do exist in nature
31
© Oxford University Press, 2013
 4. Chemical Bonding??
Inter-molecular Intra-molecular
Ionic bond COVALENT

Hydrogen bond
 ,  , …
Van der Waals

Dipole-dipole

Etc. Dipole- Induced dipole

Instantaneous dipole-induced dipole London Dispersion

Ion-dipole

Relative strengths
Ikatan ionik > Ikatan hidrogen > dipol-dipol > gaya london

© Oxford University Press, 2013

 1-Electrostatic or ionic bond
(link: Ionic bonding)

 Strongest of the intermolecular bonds (20-40 kJ mol-1)

 Takes place between groups of opposite charge
 The strength of the ionic interaction is inversely proportional to the
distance between the two charged groups
 Stronger interactions occur in hydrophobic environments
 Ionic bonds are the most important initial interactions as a drug enters
the binding site

O
Drug Drug NH3 O
O H3N Target Target
O

© Oxford University Press, 2013

 2-Hydrogen Bonds (Link: Hydrogen Bonding)

• Definisi :
Sejenis gaya tarik antar molekul yang terjadi antara
dua muatan listrik parsial dengan polaritas yang
berlawanan

• Apa yang Mempengaruhi Ikatan Hidrogen?

Kekuatan ikatan hidrogen ini dipengaruhi oleh
perbedaan elektronegativitas antara atom-atom dalam
molekul tersebut. Semakin besar perbedaannya, semakin
besar ikatan hidrogen yang terbentuk.

© Oxford University Press, 2013

2-Hydrogen Bonds
 Vary in strength
 Weaker than electrostatic interactions but stronger than van der Waals
interactions
 A hydrogen bond takes place between an electron deficient hydrogen
and an electron rich heteroatom (O, N or F)
 The electron deficient hydrogen is attached to a heteroatom (O, N or F)
 The electron deficient hydrogen is called a hydrogen bond donor (HBD)
 The electron rich heteroatom is called a hydrogen bond acceptor (HBA)

Hydrogen bond Hydrogen bond

- + -
- + - Drug Y H X
X H Y Target Target
Drug
HBD HBA HBA HBD
© Oxford University Press, 2013
2-Hydrogen Bonds

 Examples of strong HBA

- carboxylate ion, phosphate ion, tertiary amine

 Examples of moderate HBA

- carboxylic acid, amide oxygen, ketone, ester, ether,
alcohol

 Examples of poor HBA

- sulfur, fluorine, chlorine, aromatic ring, amide
nitrogen, aromatic amine

 Example of good HBD

- Quaternary ammonium ion
© Oxford University Press, 2013
 Mekanisme Terjadinya Ikatan Hidrogen

• Ikatan hidrogen terjadi ketika sebuah molekul memiliki

atom F, O, atau N yang mempunyai pasangan elektron
bebas (lonepair electron).
• Hidrogen dari molekul lain akan berinteraksi dengan
pasangan elektron bebas ini membentuk suatu ikatan
hidrogen

© Oxford University Press, 2013

 3. Van der Waals interactions (link file van der waals)

• Very weak interactions (2-4 kJ mol -1)

• Occur between hydrophobic regions of the drug and the target
• Transient areas of high and low electron densities cause
temporary dipoles
• Interactions drop off rapidly with distance
• Drug must be close to the binding region for interactions to
occur
• The overall contribution of van der Waals interactions can be
crucial to binding

DRUG
Hydrophobic regions

d+ d- Transient dipole on drug d+ d-

van der Waals interaction

d- d+
Binding site

© Oxford University Press, 2013

 3.a. Dipole-dipole interactions
• Can occur if the drug and the binding site have dipole
moments
• Dipoles align with each other as the drug enters the binding
site
• Dipole alignment orientates the molecule in the binding site
• Orientation is beneficial if other binding groups are positioned
correctly with respect to the corresponding binding regions
• Orientation is detrimental if the binding groups are not
positioned correctly
• The strength of the interaction decreases with distance more
quickly than with electrostatic interactions, but less quickly
than with van der Waals interactions

© Oxford University Press, 2013

3.a. Dipole-dipole interactions
d- O Dipole moment

d+ C
R R

Localised
dipole moment R O
C

Binding site Binding site

© Oxford University Press, 2013

 3.b. Ion-dipole interactions

• Occur where the charge on one molecule interacts with the

dipole moment of another
• Stronger than a dipole-dipole interaction
• Strength of interaction falls off less rapidly with distance
than for a dipole-dipole interaction

R O d-
C
d+
R R O d-
C
d+
O H3N
O C R

Binding site Binding site

© Oxford University Press, 2013

 3.c. Induced dipole interactions
• Occur where the charge on one molecule induces a dipole
on another
• Occur between a quaternary ammonium ion and an
aromatic ring

d+
+
R NR3 d-

Binding site

© Oxford University Press, 2013

 4. Desolvation penalties
• Polar regions of a drug and its target are solvated prior to
interaction
• Desolvation is necessary and requires energy
• The stabilisation energy gained by drug-target interactions must
be greater than the energy penalty required for desolvation
H O
H O
H H H
O O O

C H C
R R H R R
H O O H O
O H O
C
H R R

Binding site Binding site

Binding site
Desolvation - Energy penalty Binding - Energy stabilisation

© Oxford University Press, 2013

 5. Hydrophobic interactions
• Hydrophobic regions of a drug and its target are not solvated
• Water molecules interact with each other and form an ordered layer
next to hydrophobic regions - negative entropy
• Interactions between the hydrophobic regions of a drug and its
target ‘free up’ the ordered water molecules
• Results in an increase in entropy
• Beneficial to binding energy

DRUG
Drug
Binding

DRUG Hydrophobic
Drug regions
Water
Binding site Binding site
Structured water layer Unstructured water
round hydrophobic regions Increase in entropy © Oxford University Press, 2013
Tugas Belajar

• Protein
• 20 macam sturktur asam amino
• Buatlah struktur molekul suatu protein
• Bisa ditanyakan pada UTS
• Bobot: 5 % dari nilai akhir

© Oxford University Press, 2013