RATIONAL DRUG DESIGN

(RANCANGAN OBAT RASIONAL)

Penemuan Obat

Penemuan obat adalah sebuah usaha yang

diarahkan pada suatu target biologis, yang
telah diketahui berperan penting dalam
perkembangan penyakit atau dimulai dari
suatu molekul dengan aktivitas biologi
yang menarik.
Hit and Lead

 A "hit" is a chemical compound that produces a

result in a preliminary biochemical test indicating
that the compound merits further study as part of a
drug discovery project.

 A "lead" is a compound that has been selected

from a group of hit compounds based on qualities
such as the intensity of the biochemical effect
that occurs when the compound is present
(efficacy), or the absence of coincidental effects
(specificity).
Penemuan Obat
• Lead discovery : Identifikasi suatu senyawa yang
mempunyai aktivitas biologis spesifik.
• Lead optimization : Aktivitas dan sifat suatu senyawa
diuji, kemudian molekul baru dirancang dan disintesis
untuk mendapatkan aktivitas atau sifat yang diinginkan
Penemuan Obat

Pendekatan untuk lead discovery (penemuan senyawa

pemandu)
 Serendipity (luck)
 Screening
 Chemical Modification
 Rational:
1. Struktur 3Dimensi target biologis (receptor-based drug design)
2. Struktur molekul kecil yang sudah terbukti aktif (pharmacophore-based
drug design)
Penemuan Obat

1. Serendipity / ketidaksengajaan
1928 Fleming mempelajari Staphylococcus, tapi terjadi
kontaminasi di plate oleh jamur. Diamati bahwa di area yang
terkontaminasi jamur mengalami lisis. Jamur memproduksi senyawa
yang menghambat pertumbuhan bakteri : penicillin
Penemuan Obat

2. Screening
Pengujian acak aktivitas biologi sejumlah besar senyawa
menghasilkan lead. Saat ini sudah berkembang inovasi untuk
sintesis banyak senyawa sekaligus (combinatorial synthesis) dan
pengujian terhadap banyak target (high-throughput screening).
Contoh: Prontosil berasal dari zat warna yang menunjukkan
aktivitas antibakteri.
Penemuan Obat
3. Chemical Modification
Metode tradisional. Suatu senyawa analog dari senyawa aktif yang
sudah diketahui, disintesis dengan modifikasi minor, menghasilkan
peningkatan aktivitas biologi.

Keuntungan dan keterbatasan :

Mendapatkan senyawa yang sangat
mirip dengan senyawa asal.
 Penemuan Obat
4. Rational Drug Design; Ex. - Cimetidine (Tagamet)
Dimulai dari target biologis yang sudah valid, dan berakhir dengan obat
yang secara optimal berinteraksi dengan target dan memicu aktivitas biologis
yang diinginkan.

Masalah: histamin memicu sekresi asam lambung. Diinginkan suatu antagonis

histamin untuk mencegah sekresi asam lambung.

Analog Histamin disintesis dengan variasi struktur (modifikasi kimiawi) dan diuji.
N-guanyl-histamine menunjukkan aktivitas antagonis = LEAD compound.
Penemuan Obat
4. Rational Drug Design
Dimulai dengan merancang senyawa yang memenuhi persyaratan spesifik.
Senyawa kemudian disintesis dan diuji. Selanjutnya molekul dirancang
kembali, disintesis & diuji .....

Dari mana persyaratan spesifik diperoleh? Dua sumber:

1. Struktur 3Dimensi target biologis (receptor-based drug design)
2. Struktur molekul kecil yang sudah terbukti aktif (pharmacophore-
based drug design)
 Penemuan Obat
Rational Drug Design - Pharmacophore-based Drug Design
• Pengujian sifat/fitur molekul2 (ligan) kecil inaktif dan fitur molekul2 kecil yang
aktif.
• Menyusun hipotesis tentang gugus fungsi apa pada ligan yang dibutuhkan
untuk aktivitas biologis, dan gugus fungsi apa yang menekan aktivitas biologis.
• Menyusun ligan baru dengan gugus fungsi/kimiawi yang diperlukan dengan
profil 3D/lokasi yang sama dengan ligan aktif. (“Mimic” the active groups)

Keuntungan: Tidak perlu mengetahui struktur target biologis

 Penemuan Obat
Rational Drug Design –
Typical Pharmacophore-based Project
• Struktur satu seri senyawa dengan aktivitas
biologi tertentu sudah diketahui. Kemudian
dirancang struktur senyawa baru dengan
aktivitas biologis yang lebih tinggi.

• Struktur umum dan khas dari semua

senyawa aktif dikumpulkan sebagai gugus
“pharmacophophore.”
• Sebuah molekul dirancang untuk
menyerupai / mimic pharmacophore.
Penemuan Obat
Rational Drug Design - Receptor-based Drug Design
• Diuji struktur 3D dari target biologis (biasanya berupa struktur kristal sinar-
ray); kalau bisa target yang sudah membentuk kompleks dengan molekul
kecil (ligan) aktif.
• Dicari gugus kimia spesifik yang berperan dalam interaksi antara protein
target dan obat.
• Merancang kandidat obat baru yang mempunyai pola interaksi yang sama
terhadap target biologis.

Keuntungan: Visualisasi memungkinkan

rancangan langsung molekul
 Penemuan Obat
Rational Drug Design –
Typical Receptor-based Project
• Struktur protein yang berhubungan
dengan kanker dalam kompleks dengan
ligan inhibitor non selektif telah diketahui.
Ini merupakan langkah awal untuk
merancang inhibitor yang lebih selektif.

• Suatu molekul dapat dirancang

mempunyai interaksi yang lebih optimal
terhadap protein target dibanding
inhibitor asli.
 Penemuan Obat

Rational Drug Design

Typical projects tidak
hanya receptor-based
saja atau
pharmacophore-based
saja; tapi menggunakan
kombinasi informasi dari
keduanya, yang
diharapkan sinergis.
LEAD STRUCTURE OPTIMIZATION
(MODIFICATION)
 DRUG DESIGN AND DEVELOPMENT

Stages
1. Identify target disease
2. Identify drug target
3. Establish testing procedures
4. Find a lead compound
5. Structure Activity Relationships (SAR)
6. Identify a pharmacophore
7. Drug design- optimising target interactions
8. Drug design - optimising pharmacokinetic properties
9. Toxicological and safety tests
10. Chemical development and production
11. Patenting and regulatory affairs
12. Clinical trials
 DRUG DESIGN AND DEVELOPMENT

1. TARGET DISEASE
Priority for the Pharmaceutical Industry
• Can the profits from marketing a new drug outweigh the
cost of developing and testing that drug?
Questions to be addressed
• Is the disease widespread?
(e.g. cardiovascular disease, ulcers, malaria)
• Does the disease affect the first world?
(e.g. cardiovascular disease, ulcers)
• Are there drugs already on the market?
• If so, what are there advantages and disadvantages?
(e.g. side effects)
• Can one identify a market advantage for a new therapy?
 DRUG DESIGN AND DEVELOPMENT

2. DRUG TARGETS
A) LIPIDS Cell Membrane Lipids

B) PROTEINS Enzymes
Carrier Proteins
Structural Proteins (tubulin)

C) NUCLEIC ACIDS DNA

RNA

D) CARBOHYDRATES Cell surface carbohydrates

Antigens and recognition molecules
 DRUG DESIGN AND DEVELOPMENT

2. DRUG TARGETS
TARGET SELECTIVITY AND SPECIFICITY

Between species
• (Antibacterial and antiviral agents)
• Identify targets which are unique to the invading pathogen
• Identify targets which are shared but which are significantly different in
structure

Within the body

• Selectivity between different enzymes, receptors etc.
• Selectivity between receptor types and subtypes
• Selectivity between isozymes
• Organ selectivity
 DRUG DESIGN AND DEVELOPMENT

3. TESTING DRUGS
• Tests are required in order to find lead compounds and
for drug optimization
• Tests can be in vivo or in vitro
• A combination of tests is often used in research
programmes (have activity at other undesired targets)
 DRUG DESIGN AND DEVELOPMENT

3. TESTING DRUGS – IN VIVO

• Carried out on live animals or humans
• Measure an observed physiological effect
• Measure a drug’s ability to interact with its target and its ability to
reach that target
• Can identify possible side effects
• Rationalisation may be difficult due to the number of factors
involved
• Drug potency - concentration of drug required to produce 50% of
the maximum possible effect
• Therapeutic ratio/index - compares the dose level of a drug
required to produce a desired effect in 50% of the test sample
(ED50) versus the dose level that is lethal to 50% of the sample
(LD50)
 DRUG DESIGN AND DEVELOPMENT

3. TESTING DRUGS – IN VIVO

• Afinity of a drug for a receptor :

measure of how strongly that
drug binds to the receptor.
• Effiacy : measure of the
maximum biological effect that a
drug can produce as a result of
receptor binding.
• The potency of a drug : the
amount of drug required to
achieve a defined biological
effect
 DRUG DESIGN AND DEVELOPMENT

3. TESTING DRUGS – IN VITRO

• Tests not carried out on animals/humans
Target molecules (e.g. isolated enzymes or receptors)
Cells (e.g. cloned cells)
Tissues (e.g. muscle tissue)
Organs
Micro-organisms (for antibacterial agents)
• More suitable for routine testing
• Used in high throughput screening
• Measure the interaction of a drug with the target but not the ability of the
drug to reach the target
• Results are easier to rationalise - less factors involved
• Does not demonstrate a physiological or clinical effect
• Does not identify possible side effects
• Does not identify effective prodrugs
 DRUG DESIGN AND DEVELOPMENT

4. THE LEAD COMPOUND

Introduction
• A compound demonstrating a property likely to be
therapeutically useful
• The level of activity and target selectivity are not crucial
• Used as the starting point for drug design and development
• Found by design (molecular modelling or NMR) or by
screening compounds (natural or synthetic)
• Active Principle - a compound that is isolated from a natural
extract and which is principally responsible for the extract’s
pharmacological activity. Often used as a lead compound.
 DRUG DESIGN AND DEVELOPMENT

Sources of Lead Compounds

Plantlife (flowers, trees, bushes)

Micro-organisms (bacteria, fungi)
A) The Natural World Animal life (frogs, snakes, scorpions)
Biochemicals (Neurotransmitters, hormones)
Marine chemistry (corals, bacteria, fish etc)

Chemical synthesis (traditional)

B) The Synthetic World
Combinatorial synthesis

C) The Virtual World Computer aided drug design

 DRUG DESIGN AND DEVELOPMENT

 Lead discovery : Identifikasi suatu senyawa

yang mempunyai aktivitas biologis spesifik.

 Lead optimization : Aktivitas dan sifat suatu

senyawa diuji, kemudian molekul baru
dirancang dan disintesis untuk mendapatkan
aktivitas atau sifat yang diinginkan.
 Target Identification Target Validation

Target Isolation, Gentechnique

Production

Etablishment of a
3D Str. of Target
Molecule Test System

Screening Virtual Screening De Novo Design

Lead Structure

Optimization No 3D Str. of Target

Candidate Pharmacophore
 Objectives

Once a lead compound has been identified:

 Must be systematically altered to obtain the
desired properties (maximize the therapeutic
index and minimize side effects)
 Alternatively, a known agonist or substrate can be
structurally modified to make an antagonist or an
inhibitor (maintaining the structural characteristics
associated with binding and specificity but not
"activation" of the biological activity)
 From the Lead Structure to Active Compound
CH3
O

Therapeutic Target

Lead Discovery N
H

H
Lead Optimization
drug design
Clinical Candidate

CH3
Commerical Drug
O
O Br

N
O
H
H3C N
N H
H
 Lipinski‘s rule of five
In order to achieve efficient oral absorption and cell
permeability, drug candidates should have:

 Less than five hydrogen bond donors (sum of OH and

NH groups)
 A molecular weight less than 500 Da
 A log P less than 5
 Less than 10 hydrogen bond acceptors (sum of O and N
atoms in the structure)
Which physicochemical Properties should An
Active Compounds has?

Solubility and Absorption: slightly soluble, slightly absorbed

C. Lipinski‘s rule of five:

Mol. mass < 500
logP < 5
Hyd. Bond donors (N-H, O-H) < 5 Influence the transport
Hyd. Bond acceptors (N, O) < 10 across membrane

Less than 8 rotateable bonds

Polar surface < 140 Å2
From the Lead Structure to Active Compound

In the optimization process of a lead structure to a clinical

active compound, the molecules will be bigger and more
lipophil

The following properties of a lead structure are desirable:

Mol. Mass < 250
Low Lipophyli (logP<3)
Possibilities of side chain
Good Affinity and selectivity
When is a molecule drug-like?

„Typical“ Pharmaka have the folowing properties:

Mol. Mass < 500
Lipophyli in the range of –2 < logP < +5
Few hyd. bond donors (< 5)
Few hyd. bond acceptors (< 10)
At least one –OH group
(Except: psychoactive Compound)

Gepard, Modern Methods in Drug Discovery

WS05/06
 Methods of Lead Optimization in Analog Design

In analog design, molecular modifications of the lead compound

can involve one or more of the following strategies
1. Identification of the active part (Pharmacophore).
2. Functional group optimization
3. Structure activity relationship studies.
4. Bioisosteric replacement.
5. Design of rigid analogs.
6. Homologation of alkyl chains or alteration of chain branching,
design of aromatic ring position isomers, alteration of ring size,
and substitution of an aromatic ring for a saturated one or the
converse.
 Methods of Lead Optimization in Analog Design

In analog design, molecular modifications of the lead compound

can involve one or more of the following strategies
7. Alteration of stereochemistry, or design of geometric isomers or
stereoisomers.
8. Design of fragments of the lead molecule that contain the
pharmacophore group (bond disconnection).
9. Alteration of interatomic distances within the pharmacophoric
group in other parts of the molecule.
 Methods of Lead Optimization in Analog Design

Identification of the active part (Pharmacophore)

 Any drug molecule consists of both, essential and nonessential
parts. Essential part is important in governing pharmacodynamic
(drug receptor interactions) property while non-essential part
influences pharmacokinetic features. The relevant groups on a
molecule that interact with receptor are known as bioactive
functional group. They are responsible for the activity. →
Pharmacophore
 Once such pharmacophore is identified, structural modifications
can be done to improve pharmacokinetic properties of the drug.
Methods of Lead Optimization in Analog Design

 Morphine, the prototype narcotic agent has a

pentacyclic structure.
 Hence the pharmacophore of morphine has been
recognized through molecular dissection and was
used to develop still similar and even acyclic analogs.
 For example, Methadone is as potent as analgesic as
morphine.
 Methods of Lead Optimization in Analog Design

Functional group optimization

 The activity of a drug can be correlated to its structure in terms
of the contribution of its functional groups to the lipophilicity,
electronic and steric features of the drug skeleton.
 Hence by selecting proper functional group, one can govern the
drug distribution pattern and can avoid the occurence of side
effects.
 For example, the amino group of carbutamide (antibacterial
agent) was replaced by a methyl group to give tolbutamide
(antidiabetic agent).
Methods of Lead Optimization in Analog Design

Similarly removal of sulfonamide

side chain chlorothiazide (an
antihypertensive drug with diuretic
activity) helped to design diazoxide
(an antihypertensive drug without
diuretic activity)
 Methods of Lead Optimization in Analog Design

Structure activity relationship studies

 The physiological action of a molecule is a function of its
chemical constitution.
 This observation is the basis of interpretation of activity in terms
of the structural features of a drug molecule.
 Generalized conclusion is then can be made after examining a
sufficient number of drug analogs.
 For example, Sulphonamides are found to be associated with
diuretic and antidiabetic activities in addition to their
antibacterial activity
 Methods of Lead Optimization in Analog Design

Bioisosteric replacement
 In medicinal chemistry, bioisosteres are chemical
substituents or groups with similar physical or
chemical properties which produce broadly similar
biological properties to another chemical compound.
 Bioisosterism is used to reduce toxicity, change
bioavailability, or modify the activity of the lead
compound, and may alter the metabolism of the
lead.
 the replacement of a hydrogen atom with a fluorine
atom at a site of metabolic oxidation in a drug
candidate may prevent such metabolism from taking
place.
 Methods of Lead Optimization in Analog Design

Design of rigid analogs

 Imposition of some degree of molecular rigidity on a
flexible organic molecule (e.g., by incorporation of
elements of the flexible molecule into a rigid ring system
or by introduction of a carbon-carbon double or triple
bond) may result in potent, biologically active agents that
show a higher degree of specificity of pharmacological
effect.
 The cyclopropane ring was employed to impart a degree
of rigidity to side chain of dopamine. Neither isomer
displayed effects at dopamine receptors, but both were
α-adrenoceptor agonists.
Methods of Lead Optimization in Analog Design

Homologation
 Series of compounds that differ by a constant unit; generally
a CH2 group -(CH2)n- where n is varied.
 Typically, an increase followed by a decrease in potency;
note that the number of CH2 groups associated with the
maximum potency differs for the series of compounds under
study.
 Changes in activity often associated with solubility/absorption
issues.
 Micelle formation of amphiphilic (lipid-like) compounds,
therefore, not available to bind at receptor. This occurs when
non-polar tails are long and polar head groups are present.
Methods of Lead Optimization in Analog Design

Chain branching of aliphatic chains

 Tends to make compounds more lipophilic
 Increased size of R-group could effect receptor binding
 Phenethylamine: good monoamine oxidase (MAO) substrate
(therefore readily degraded) versus alpha-
methylphenethylamine (amphetamine), which is a poor
substrate
 Upon going from phenethylamine to amphetamine both the
bioavailability and activity is altered.
Methods of Lead Optimization in Analog Design

Chain branching
Changing 10-aminoalkylphenothiazine R groups:
S

1) -CH2CH(CH3)N(CH3)2 (promethazine)
N X
2) -CH2CH2N(CH3)2 (diethazine)
R
for 1 and 2: antispasmodic and antihistaminic
3) -CH2CH2CH2N(CH3)2 (promazine) decreased antispasmodic and
antihistaminic activities, has sedative and tranquilizing activities
4) -CH2CH(CH3)CH2N(CH3)2 (trimeprazine) reduced tranquilizing
activity, antipruritic (anti-itch) activity
Methods of Lead Optimization in Analog Design

Ring-Chain Transformations
 Change alkyl substituent into cyclic analogs (or vice versa).
 The following two drugs, trimeprazine and methdilazine, are
equivalent as antipruritic agents in humans.
Trimeprazine
S
X = Cl
R = CH2CH(CH3)CH2N(CH3)2

N X Methdilazine
CH3
X=H
R H2 N
R= C
Methods of Lead Optimization in Analog Design

Fragments of the lead molecule

The analgesic pharmacophore of morphine has
been defined as the basic nitrogen atom, the
aromatic ring three carbon atoms from the
nitrogen, and a quaternary carbon adjacent to
the aromatic ring.