DRUG DESIGN (AN OVERVIEW)
Drug Design & Discovery: Introduction
Drugs: Targets:
Natural sources Synthetic sources
Discovering and Developing the
‘One Drug’
Profile of Today’s Pharmaceutical Business
•Time to market: 10-12 years. By contrast, a chemist develops a
new adhesive in 3 months! Why? (Biochemical, animal, human
trials; scaleup; approvals from FDA, EPA, OSHA)
Pharmaceutical R&D
A Multi-Disciplinary Team
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Oncology Organic Chemistry Pathology Peptide Chemistry Pharmacokinetics Pharmacology Photochemistry
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Technical Information Toxicology Transdermal Drug Delivery Veterinary Science Virology X-ray Spectroscopy
Medicinal chemists today are facing a
serious challenge because of the
increased cost and enormous amount of
time taken to discover a new drug, and
also because of fierce competition
amongst different drug companies
Drug Discovery & Development
Identify disease Drug Design
- Molecular Modeling
- Virtual Screening
Find a drug effective
against disease protein
Isolate protein (2-5 years)
involved in Scale-up
disease (2-5 years)
Preclinical testing
(1-3 years) Human clinical trials
D
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(2-10 years)
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Formulation
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FDA approval
(2-3 years)
Drug Discovery overview
Approaches to drug discovery:
•Serendipity (luck)
•Chemical Modification
•Screening
•Rational
Serendipity “Chance favors the prepared mind”
1928 Fleming studied Staph, but contamination of plates with
airborne mold. Noticed bacteria were lysed in the area of mold.
A mold product inhibited the growth of bacteria: the antibiotic
penicillin
Chemical Modifications
(A) Homolog Approach: Homologs of a lead prepared
R-(CH2)n-N Homologs (n=2,3,4,5.....)
(B) Molecular Disconnection /Simplification
N CH3
CH2OCONH2
H3C
NCH2CH=C C C3H7
CH2OCONH2
HO O
MORPHINE PENTAZOCINE MEPROBAMATE
(C) Molecular Addition (D) Isosteric Replacements
N-CH2-CH=CH2
H2N COOH H2N SO2NH2
P.A.B.A. SULFANILAMIDE
HO O
NALORPHINE
Chemical Modification….
•Traditional method.
• An analog of a known, active compound is synthesized with a
minor modification, that will lead to improved Biological Activity.
Advantage and Limitation: End up with something very similar
to what you start with.
Screening
Testing a random and large number of different molecules for
biological activity reveals leads. Innovations have led to the
automation of synthesis (combinatorial synthesis) and testing
(high-throughput screening).
Example: Prontosil is derived from a dye that exhibited
antibacterial properties.
First generation Rational
approach in Drug design
In 1970s the medicinal chemists
considered molecules as topological
entities in 2 dimension (2D) with
associated chemical properties.
QSAR concept became quite popular.
It was implemented in computers and
constituted first generation rational
approach to drug design
2nd generation rational drug design
The acceptance by medicinal chemists
of molecular modeling was favored by
the fact that the QSAR was now
supplemented by 3D visualization.
The “lock and key” complementarity is
actually supported by 3D model.
Computer aided molecular design
(CAMD) is expected to contribute to
intelligent lead
MECHANISM BASED DRUG-DESIGN
• Most rational approach employed today.
• Disease process is understood at molecular level & targets are well
defined.
• Drug can then be designed to effectively bind these targets & disrupt
the disease process
• Very complex & intellectual approach & therefore requires detailed
knowledge & information retrieval. (CADD Holds Great Future)
“Drug –Receptor Interaction is not merely a lock-key interaction but a
dynamic & energetically favorable one”
Evolutionary drug designing
Ancient times: Natural products with
biological activities used as drugs.
Chemical Era: Synthetic organic
compounds
Rationalizing design process: SAR &
Computational Chemistry based Drugs
Biochemical era: To elucidate biochemical
pathways and macromolecular structures
as target as well as drug.
New Targets
Total Druggable
Genome genes
Includes biological Space
Small molecule Space
New druggable space ?
Existing drugs (450 Targets)
targets)
~30,000 ~3,000
HIGH-THROUGHPUT SCREENING
FUNCTIONAL INTEGRATION OF:
BIOLOGY
CHEMISTRY
SCREENING TECHNOLOGY
INFORMATICS
BOTTLENECKS
Hundreds of “Hits” but NO “Leads”
Data mining
Accurate profiling of molecules for
further studies.
Smart Drug Discovery platform
A view of Drug Discovery road map illustrating some key multidisciplinary
technologies that enable the development of (a) Breakthrough medicines from
promising candidates (b) LO & generation processes that are relative to novel
ligands.
Tomi K Sawyer, Nature Chemical Biology 2, (12) December
2006.
Molecular Modeling
NMR and X-ray QSAR/3D QSAR
structure determination Structure-based drug design
Rational drug design
Model construction
Molecular mechanics
QM, MM methods Homology modeling
Conformational searches
Molecular dynamics
Combinatorial chemistry Bioinformatics
Chemical similarity Chemoinformatics
Chemical diversity
What is Molecular Modeling?
Molecular Graphics: Visual representation of
molecules & their properties.
Computational Chemistry: Simulation of
atomic/molecular properties of compound
through computer solvable equations.
( b’-b’0)[ V1cos] b’ (-0) [V1cos]
Statistical Modeling: D-R, QSAR/3-D QSAR Molecular data
Information Management: Organizational databases
retrieval /search & processing of properties of 1000… of
compounds.
MM = Computation + Visualization + Statistical modeling
+ Molecular Data Management
When Newton meets Schrödinger...
Sir Isaac Newton Erwin Schrödinger
(1642 - 1727) (1887 - 1961)
F ma Ĥ