The Drug Discovery

Elly Usman

Bahagian Farmakologi dan Terapeutik

Fakultas Kedokteran Universitas Andalas
Drug Discovery from Plant
 Uji bioaktivitas
 Dereplikasi
 Analisis Struktur dari isolat
 Pengembangan Senyawa Aktif
 Ekstraksi
 Fraksinasi
 Uji Bioaktivitas
 Uji Skrining
untuk mendeteksi keberadaan senyawa
aktif dalam ekstrak
 Uji Monitoring
untuk menelusuri konstituen aktif selama
proses isolasi
 Dereplikasi
 Adalah teknik untuk menghindari isolasi
senyawa yang telah diteliti/ diketahui
sebelumnya.
 Dapat dilakukan dengan teknik skrining kimia
menggunakan kromatografi, NMR,
spektroskopi UV-vis, dan hasilnya
dibandingkan dengan database
Tahapan Dereplikasi
 Analisis Struktur dari Isolat
 Struktur molekul dari isolat yang diperoleh dari
fraksinasi ditentukan dengan analisis kombinasi dari
data Mass Spectrometry, Nuclear Magnetic
Resonance, Infra Red, UV-vis.
 Namun demikian, fraksi aktif kadang masih berupa
campuran sehingga penetuan struktur bisa dibantu
dengan teknik tandem, GC-MS, LC-UV, LC-MS, LC-
NMR dan LC-DAD. Dalam prosedur ini campuran
sebelumnya akan dipisahkan dan kemudian masuk
ke tahap spektrokopi.
Pengembangan Senyawa Aktif
 Sintesis senyawa aktif dari bahan alam
terkadang menjadi sangat mahal ketika
berurusan dengan senyawa aktif dengan
banyak atom karbon kiral. Sehingga proses
produksi dilakukan dengan peningkatan
produksi tanaman atau mikroorganisme
sumber senyawa aktif tersebut.
 Ekstraksi
 Ekstraksi adalah proses awal dalam separasi
senyawa yang diinginkan dari bahan awal.
 Prosedur ekstraksi disesuaikan dengan
tujuan ekstraksi, skala, jenis, uji skrinning dan
jenis senyawa yang akan diekstraksi.
 Pelarut dalam ekstraksi

Polaritas Pelarut Kelas Senyawa

Rendah Heksana Lipid, lilin, minyak atsiri
Kloroform Alkaloid, aglikon
Eter Alkaloid dan aglikon
Etanol Glikosida
Tinggi Air Asam amino, gula, dan
glikosida
 Metode Ekstraksi
 Penggunaan panas
 Distilasi uap
 Supercritical fluid extraction
 pembersihan
 Fraksinasi
 Metode fraksinasi yang paling umum
digunakan adalah partisi dan kromatografi.
 Metode lain yang jarang dipakai adalah
pengendapan, fraksinasi ditilasi, distilasi uap
dan dialisis.
Target selection & Discovery Development
validation

Target Drug Candidate

Studies of -receptor; -ion channel; -transporter; safety testing
-enzyme; - signalling molecule
Disease Mechanisms

Lead Search
-Develop assays (use of automation) Human Studies
-Chemical diversity Phases I,II, III
Molecular Studies -Highly iterative process

Animal Studies
- relevant species
Drug Approval
- transgenic KO/KI mice Lead optimization and Registration
-selectivity
- conditional KOs
-efficacy in animal models
- agonists/antagonists
-tolerability: AEs mechanism-
- antibodies based or structure-based?
- antisense -pharmacokinetics
- RNAi -highly iterative process
 Target Selection & Validation
 Define the unmet medical need (disease)
 Understand the molecular mechanism of the
disease
 Identify a therapeutic target in that pathway (e.g
gene, key enzyme, receptor, ion-channel,
nuclear receptor)
 Demonstrate that target is relevant to disease
mechanism using genetics, animal models, lead
compounds, antibodies, RNAi, etc.
 Discovery
 Develop an assay to evaluate activity of compounds on the target
- in vitro (e.g. enzyme assay)
- in vivo (animal model or pharmacodynamic assay)
 Identify a lead compound
– screen collection of compounds (“compound library”)
– compound from published literature
– screen Natural Products
– structure-based design (“rational drug design”)
 Optimize to give a “proof-of-concept” molecule—one that shows efficacy
in an animal disease model
 Optimize to give drug-like properties—pharmacokinetics, metabolism,
off-target activities
 Safety assessment, Preclinical Candidate!!!
 Development
Pre-Clinical
Process R&D
Pharmacology Chem Eng. R&D
Safety Assessment Manufacturing
Toxicology
Drug Metabolism
(ADME)

Pharmaceutical R&D
Formulation Bio Process R&D

Clinical Investigator
& patient
Regulatory Affairs
Clinical Pharmacology Project Planning & Management
Clinical Research Marketing

Statistics & Epidemiology

Data Coordination
Research Information Systems
Information Services
Clinical
 Phase I Product Profile Marketing SOI
Investigational
20 - 100 healthy volunteers take
New Drug drug for about one month
application Information Learned

IND 1. Absorption and metabolism

2. Effects on organs and tissue
3. Side effects as dosage is increased

Remote data entry

Clinical Phase II
Trials Several hundred health-impaired patients Information Learned
1. Effectiveness in treating disease
Treatment Group Control Group 2. Short-term side effects in health -impaired patients
3. Dose range

Phase III Information Learned

1. Benefit/risk relationship of drug
Hundreds or thousands of health- 2. Less common and longer term side effects
impaired patients 3. Labeling information

Compassionate Use
 Clinical Advisory
Committee Regulatory
Trials Review Team
Continued
APPROVAL
Reviews,
PROCESS comments, and
(Ex. FDA)
discussions
Submit to
Regulatory Agencies
Drug Co./Regulatory
liaison activities
New Drug
Application
(NDA)
APPROVAL

Worldwide Marketing Authorization (WMA) in other countries

 Drug Discovery—Convergence of Disciplines
Synthetic
Combinatorial Patent Law
Chemistry
Chemistry
Modelling
Novel
Intellectual Property
Molecule Physiology
Information Design Structural Biochemistry
Technology
Activity
Physiology
Safety Pharmaco- Physiology
Metabolism
dynamics Pharmacology
Safety
Assessment Immunology
In Vivo activity Pharmacokinetic
Properties DMPK

Pharmacology Behavior
Pathology Enzymology
Physiology Physical Physiology
Chemistry
Genomics involved in drug Bioinformatics involved in
discovery drug discovery
Proteomics involved in drug discovery
Terima Kasih