V What is drug design ?

V How drug can be designed ?

rational drug design
structure based drug design
computer assisted drug design
3D- QSAR

V Examples of drug design

Zanamivir
V References
V Drug design is the approach of finding drugs by design,
based on their biological targets. Typically a drug target is a
key molecule involved in a particular metabolic or signalling
pathway that is specific to a disease condition or pathology,
or to the infectivity or survival of a microbial pathogen.
V Some approaches attempt to stop the functioning of the
pathway in the diseased state by causing a key molecule to
stop functioning.
V Drugs may be designed that bind to the active region and
inhibit this key molecule. However these drugs would also
have to be designed in such a way as not to affect any other
important molecules that may be similar in appearance to
the key molecules.
V Sequence homologies are often used to identify such risks.
V !ther approaches may be to enhance the normal pathway
by promoting specific molecules in the normal pathways that
may have been affected in the diseased state.
V The structure of the drug molecule that can specifically interact
with the biomolecules can be modeled using computational
tools. These tools can allow a drug molecule to be constructed
within the biomolecule using knowledge of its structure and the
nature of its active site.
V Construction of the drug molecule can be made inside or
outside in depending on whether the core or the R-groups are
chosen first. However many of these approaches are plagued
by the practical problems of chemical synthesis.
V Newer approaches have also suggested the use of drug
molecules that are large and proteinaceous in nature rather
than as small molecules.
V There have also been suggestions to make these using mRNA.
Gene silencing may also have therapeutical applications.
V Rational drug design
V Structure based drug design
V Computer assisted drug design
V 3D- QSAR
V anlike the historical method of drug discovery, rational drug
design begins with a knowledge of specific chemical
responses in the body or target organism, and making
combinations of these to fit a treatment profile.
V Because of the complexity of the drug design process two
terms of interest are still serendipity and bounded rationality.
Those challenges are caused by the large chemical space
describing potential new drugs without side-effects.
V A particular example of rational drug design involves the use
of three-dimensional information about biomolecules
obtained from such techniques as x-ray crystallography and
NMR spectroscopy. This approach to drug discovery is
sometimes referred to as structure-based drug design.
V The first example of the application of structure-based drug
design leading to an approved drug is the carbonic
anhydrase inhibitor dorzolamide which was approved in 1995
V Another important case study in
rational drug design is imatinib, a
tyrosine kinase inhibitor designed
specifically for the à
à fusion
protein that is characteristic for
Philadelphia chromosome-positive
leukemias (CML and ALL).
V umatinib is substantially different
from previous drugs for cancer as
most agents of chemotherapy
simply target rapidly dividing cells,
not differentiating between
cancer cells and other tissues.
V un structure-based drug design, the
three-dimensional structure of a drug
target interacting with small molecules
is used to guide drug discovery.
V Structure-based drug design
represents the idea that you can see
exactly how your molecule interacts
with its target protein.
V Structure-based drug design was
equated with de novo design or
building a molecule from the ground
up. The active site of the protein was a
space to be filled with a molecule that
complemented it in terms of shape,
charge, and other binding
components.
V un structure-
structure-based drug design, scientists use
detailed knowledge of the active sites of
protein targets associated with particular
diseases to design synthetic compounds that
fight the disease.
V The active site of an enzyme is the area into
which a chemical or biological molecule fits
to initiate a biochemical reaction.
V Structure
Structure--based drug design aims to create a
molecule that will bind to the active site of a
targeted enzyme, thereby preventing the
normal chemical reaction and ultimately
halting the progression of the disease.
V Crystallography, is the scientific discipline that is at the center of
structure-based drug design. Crystals are solid substances with
symmetrically arranged molecules.
V !btaining large, well-ordered crystals is essential for a
crystallographer to be able to analyze the three-dimensional
molecular structure and active site of the proteins that control
cellular biology.
V BioCryst's scientists use X-ray crystallography throughout the
process of designing and optimizing potential drugs.
V First, they use crystallography to determine the structure of their
target proteins. This structure is used to design potential
compounds that will fit the active site of the target.
V Scientists then use crystallography to study how compounds bind
with the active site of the target protein. asing information
gained through crystallography, researchers refine the
compounds to improve their performance
V Traditionally, scientists identify new drugs either
by fiddling with existing drugs or by testing
thousands of compounds in a laboratory. uf you
think of the target molecule as a lock, this
approach is rather like trying to design a key
perfectly shaped to the lock.
V asing a structure-based strategy, researchers
have an initial advantage. They start with a
computerized model of the detailed, three-
dimensional structure of the lock and of its key.
V Then scientists try to design a molecule that will
plug up the lock to keep out the substrate key.
Œnowing the exact three-dimensional shape of the lock, scientists
can discard any of the metal scraps (small molecules) that are not
the right size or shape to fit the lock. They might even be able to
design a small molecule to fit the lock precisely. Such a molecule
may be a starting point for pharmaceutical researchers who are
designing a drug to treat Hu infection
V Computer-assisted drug design uses computational
chemistry to discover, enhance, or study drugs and
related biologically active molecules.
V Methods used can include simple molecular
modeling, using molecular mechanics, molecular
dynamics, semi-empirical quantum chemistry
methods, ab initio quantum chemistry methods and
density functional theory.
V The purpose is to reduce the number of targets for a
good drug that have to be subjected to expensive
and time-consuming synthesis and trialling.
V Quantitative Structure-Activity Relationship(QSAR) studies are
widely used in drug design, in particular, for hit-to-lead and lead
optimizations.
V Ouantitative structure-activity relationship (O
 is the process
by which chemical structure is quantitatively correlated with a
well defined process, such as biological activity or chemical
reactivity.
V For example, biological activity can be expressed quantitatively
as in the concentration of a substance required to give a certain
biological response.
V Additionally, when physicochemical properties or structures are
expressed by numbers, one can form a mathematical
relationship, or quantitative structure-activity relationship,
between the two. The mathematical expression can then be
used to predict the biological response of other chemical
structures.
V QSAR's most general mathematical form is:
Activity = i(physiochemical properties and/or structural properties)
V Cimetidine, the prototypical H2-receptor antagonist
from which the later members of the class were
developed
V Dorzolamide, a carbonic anhydrase inhibitor used to
treat glaucoma
V Many of the atypical antipsychotics
V Selective C!X-2 inhibitor NSAuDs
V SSRus (selective serotonin reuptake inhibitors), a class
of antidepressants
V Zanamivir, an antiviral drug
V Enfuvirtide, a peptide Hu entry inhibitor
V Probenecid
V Nonbenzodiazepines like Zolpidem and Zopiclone
V Relenza (zanamivir), an anti-viral drug, for
persons aged 7 years and older for the
treatment of uncomplicated influenza
illness. This product is approved to treat
type A and B influenza, the two types most
responsible for flu epidemics.
V The drug works by destroying an enzyme,
neuraminidase, on the surface of the virus,
essential for the multiplication and spread
of influenza. Relenza is not a vaccine.
V 3

 
à

Zanamivir was the first of a new
generation of drugs known as
neuraminidase inhibitors, capable of
treating or preventing infection from
the influenza virus.
V Neuraminidase is essential for the
replication of all influenza viruses. ut
is an enzyme which allows new
viruses to be released from the
infected lung cells, further extending
the infection. Neuraminidase
inhibitors block this activity,
preventing the release and spread
of new viruses.
V Clinical studies showed that for the
drug to be effective, patients
needed to start treatment within two
days of the onset of symptoms.
V The drug seemed to be less effective
in patients whose symptoms weren't
severe or didn't include a fever.
V Relenza is approved for preventive
use, to decrease the risk of
developing influenza illness, for
persons aged 5 and older. Relenza
has not been proven effective for
prevention of influenza in nursing
home patients.
V http://en.wikipedia.org/wiki/Drug_design
V http://www.proxychem.com/sbdd.html
V http://www.biocryst.com/structure_baseddrug
design.htm
V http://pubs.acs.org/cen/coverstory/7923/7923
drugdesign.html
V http://www.netsci.org/Science/Compchem/fe
ature12.html
V http://www.fda.gov/cder/news/relenza/defaul
t.htm
V http://www.chemosoft.com/modules/drug_de
sign/qsar/