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Kannan Drugdesign PT

Drug design is a systematic approach to finding and optimizing drug molecules based on their molecular interactions with target proteins. There are two main approaches: ligand-based design which uses knowledge of existing ligands, and structure-based design which uses 3D structural information of the target. Key techniques in drug design include quantitative structure-activity relationships (QSAR), analog design, combinatorial chemistry, pharmacophore modelling, and molecular docking. The goal is to design ligands that strongly and selectively bind to the target receptor through interactions like hydrogen bonding and hydrophobic effects.

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Kannan Kathuria
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87 views16 pages

Kannan Drugdesign PT

Drug design is a systematic approach to finding and optimizing drug molecules based on their molecular interactions with target proteins. There are two main approaches: ligand-based design which uses knowledge of existing ligands, and structure-based design which uses 3D structural information of the target. Key techniques in drug design include quantitative structure-activity relationships (QSAR), analog design, combinatorial chemistry, pharmacophore modelling, and molecular docking. The goal is to design ligands that strongly and selectively bind to the target receptor through interactions like hydrogen bonding and hydrophobic effects.

Uploaded by

Kannan Kathuria
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ROLE OF DRUG

DESIGN IN DRUG
DEVELOPMENT
PRESENTED BY : KANNAN
M.PHARMACY (PHARMACEUTICAL
CHEMISTRY)
SPER, JAMIA HAMDARD
WHAT IS DRUG DESIGN ?
Drug Design is a systematic approach to finding, selection, optimization of drug molecules on
the basic of molecular interactions (Strero-structural basis) between drug and target proteins.
Frequently the drug design is based on a computer modeling technique known as computer-
aided drug design (CADD).
In CADD attempts are made to find a ligand that will interact favorably with a receptor or target
protein that represents the target site.
Binding of ligand to the receptor may include hydrophobic, electrostatic, and hydrogenbonding.
The approach used in CADD is dependent upon the amount of information that is available
about the ligand and receptor. Ideally, one would have 3-dimensional structural information for
the receptor and the ligand-receptor complex from X-ray diffraction or NMR.
TYPES OF DRUG DESIGN
There are two major types or approaches to drug design.
1. Ligand based drug design (Indirect drug design) :Ligand based drug design is based on the
knowledge of other molecules that bind to the biological target of interest so as to derive a
pharmacophore which will bind to the target.
(A) QSAR
(B) Analog drug design
(C) Combinatorial chemistry
(D) Natural Products as a lead, etc
2. Structure based drug design (Direct drug design): Structure based drug design is based on the
knowledge of the three dimensional structure of the biological target. Using the structure of the
biological target, candidate drugs that are predicted to bind with high affinity and selectivity to
the target may be designed.
QSAR(Quantitative Structure Activity
Relationships)
QSAR is mathematical or statistical approaches
to define the relationship between biological
activity (experimental data)of a molecular system
and its geometrical, physical, electronic, and
chemical properties
Activity = function (property 1 , property 2…..)
Property- geometry, steric etc
ANALOGUE DRUG DESIGN
Analog design is most fruitful in the study of pharmacologically active molecules that are
structurally specific: their biological activity depends on the nature and the details of their
chemical structure.
Hence, a minor modification of the molecule may result in a profound change in the
pharmacological response (increase, diminish, completely destroy, or alter the nature of the
response).
Lead compounds are frequently identified as endogenous participants (hormones,
neurotransmitters, second messengers, or enzyme cofactors) in the body's biochemistry and
physiology.
A lead may result from routine, random biological screening of natural products or of synthetic
molecules that were created for purposes other than for use as drugs.
In analog design, molecular modification of the lead compound can involve one or more of the
following strategies:
1. Bioisosteric replacement: The structural similarity between imipramine and the phenothiazine
antipsychotics.

2. Design of rigid analogs


3. Homologation of alkyl chain(s) 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
4. Alteration of stereochemistry, or design of geometric isomers (or) stereoisomers
5. Design of fragments of the lead molecule that contain the pharmacophoric group (bond
disconnection)
6. Alteration of interatomic distances within the pharmacophoric group or in other parts of the
molecule A lead may result from routine, random biological screening of natural products or of
synthetic molecules that were created for purposes other than for use as drugs.
COMBINATORIAL
CHEMISTRY
Combinatorial chemistry comprises chemical synthetic methods that make possible to prepare large number (tens
to thousands or even millions) of compounds in a single process.
These compound libraries can be made as mixtures, sets of individual compounds or chemical structures
generated in computer.
NATURAL PRODUCT
AS A LEAD
Lead is the prototype bioactive molecule subjected to drug design and drug
discovery and needs to exploration and exploitation.
A total no. of 520 new pharmaceuticals approved between 1983 and 1994,
among which 39% were derived from natural products, the proportion of
antibacterials and anticancer agents of which was over 60%.
Between 1990 and 2000, a total of 41 drugs derived from natural products were
launched on the market by major pharmaceutical companies including
azithromycin, orlistat, paclitaxel, sirolimus (rapamycin), Synercid, tacrolimus, and
topotecan.
TYPES OF
STRUCTURE BASED
DRUG DESIGN
The ultimate goal of structure-based drug design is a
simple robust process that starts with high
resolution crystal structure of a validated biological
macromolecular target and reliably generates an
easily synthesized, high-affinity small molecule with
desirable pharmacological properties.
TYPES :
A) COMPUTERISED DRUG DESIGN
B) RATIONAL DRUG DESIG
COMPUTERISED DRUG
DESIGN
1. hit identification: using virtual screening
(structure- or ligand-based design)
2. hit-to-lead optimization: affinity and selectivity
(structure-based design, QSAR, etc.)
3. lead optimization:
optimization of other pharmaceutical
properties while maintaining affinity
RATIONAL DRUG DESIGN
A drug target is a key molecule involved in a particular metabolic or signaling pathway that is specific to a
disease condition or pathology or to the infectivity or survival of a microbial pathogen.
The first unequivocal 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.
Another important case study in rational drug design is imatinib, a tyrosine kinase inhibitor.
PHARMACOPHORE
MODELLING
“A pharmacophore is the pattern of
features of a molecule that is responsible
for a biological effect, Each atom or group
of a compound that shows features
associated with molecular recognition can
be converted into a pharmacophore
pattern. Molecular pharmacophore
patterns can be hydrogen bond donor
positive features, negative features,
aromatic rings, hydrophobic features and
their combination.
MOLECULAR
DOCKING
Molecular docking is a computational method to identify the architecture of compounds
generated by two or more distinct molecules.
Docking is widely used to anticipate the interaction between ligand and target protein in terms
of affinity and activity. Docking plays a critical role in rational drug design. Considering the
biological and pharmacological importance of docking studies, much effort has been made to
improve the algorithms for docking prediction.
Docking is a mathematical technique that anticipates the preferable orientation of one
molecule (may be drug, which has ligand) relative to another (may be target protein, which has
binding site) when they are linked together to create a stable complex.
Using scoring functions (binding energy), it is possible to estimate the strength of the
connection or binding affinity across two compounds based on their preferential orientation.
Rigid docking
Assuming the compounds are inflexible, we are
seeking a rearrangement of one of the compounds in
three-dimensional space that results in the best
match to the other compounds in parameters of a
scoring system. The ligand’s conformation can be
formed with or without receptor binding activity.
Flexible docking
In conjunction with transformation, we evaluate
molecular flexibility to identify confirmations for the
receptor and ligand molecules as they exist in the
complex.
THANK YOU

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