Drug targets and drug

designing
Presented to:
Mam Huma Ahmed
Group members:

• Adil Anwar 1031.

• Aqsa Maqsood 1043.
• Aqsa Malik 1048.
• Meera Ahmed 1062.
• Usama Tahir 1066.
• Namrah Zia 1075.
Contents

• Drug targets and its types.

• Drug designing
• Types of drug designing.
• Introduction to computational chemistry and molecular modeling.
• Computer aided drug design.
Drug targets:

• Drug target is a molecule in the body, usually a protein, that is intrinsically associated
with a particular disease process and that could be addressed by a drug to produce a
desired therapeutic effect.
• Biological target: A biological target is anything with in a living organism to which
some other entity(like an endogenous ligand or a drug) is directed and/or binds, resulting
in a change in its behavior or function.
Types of drug targets-Most common drug targets:

• Proteins(45%):
G-protein coupled receptors.
• Enzymes(28%):
especially protein kinases, proteases, esterases, and phosphatases.
• Ion Channels(5%):
Ligand gated ion channel.
Voltage gated ion channel.
• Nuclear hormone receptors(11%).
• Nucleic acid(2%).
Drug design:

• Drug design is the inventive process of finding new medications based on the knowledge
of a biological target.
• Drug design is defined as:

the design of molecules that are complementary in shape and charge to the
bimolecular target with which they interact and therefore will bind to it.
Stages involved in drug design:

• Early discovery stage:

1. Identify target disease.
2. Discovery of new chemical entity.
3. Find lead compound.
4. Structure activity relationship.
5. Identify pharmacophore.
6. Identify drug targets.
Stages:
continued…
• Preclinical trials
• Investigational new drug application stage.
• Production formulation.
• Clinical trails.
• New Drug Application – NDA.
• Post marketing surveillance.
Computer-Aided drug design:

• Computer aided drug design encompasses the techniques that use computational
chemistry to study drugs and related biologically active molecules.
• Also famous from the name “computational chemistry”
• Diverse computational chemistry approaches are use to calculate and predict events such
as drug binding to its target and the chemical properties for designing potential new drug.
Uses of CADD:

Computer-aided methods are being utilized to:

• Speed up hit identification.
• Facilitate hit-to-lead selection.
• Optimize various drug parameters (absorption, distribution, metabolism, excretion and
toxicity profile).
• Avoid safety issues.
 Benefits:

• TIME SAVING: The process of drug discovery and development is a long and difficult
one, and the costs of developing are increasing rapidly. Today it takes appropriately 10years
and $100million to bring a new drug to market.
• REDUCED COST: The use of new computer-based drug design techniques has the ability
to accomplish both of these goals and to improve the efficiency of the process as well, thus
reducing costs.
• IMPROVE QUALITY OF LIFE: The emphasis now is not just on finding new ways to
treat human disease, but also on improving the quality of life of people in general.
Types of drug designing:

• Structure-based Drug Design.

• Ligand based Drug Design.
Ligand based drug design(LBDD):

• When there is a natural ligand present in a protein, the features of that protein or already
proposed ligands' features are used to design a new ligand that has more affinity than the
existing ones is said to be Ligand based.
• Used to derive a pharmacophore.
• Relies on knowledge of other molecules that bind to the biological target of interest. Also
known as INDIRECT DRUG DESIGN.
Approaches for LBD

1. Molecular fingerprint and similarity searching.

2. Pharmacophore modeling.
3. Quantitative structure activity relationship.
Molecular fingerprint and similarity searches:

• These techniques attempt to represent molecules in such a way as to

allow rapid structural comparison in an effort to identify structurally
similar molecules.
• Consider all parts of the molecules rather focusing on the part thought to
be the most important for activity
Pharmacophore modeling:

A pharmacophore model explains how structurally diverse ligands can bind to a common
receptor site.
Furthermore pharmacophore models can be used to identify through denovo design or
virtual screening novel ligands that will bind to the same receptor.
QSAR

It is a process f studying series of molecules of different structure and properties and

attempting to find empirical relationship.

CoMFA and CoMSIA:

these are the 3D-QSAR technique that align molecules and extract aligned features that can be related
to biological activity.
Structure base drug design:

• SBDD is a process based on knowledge of 3D structure of drug/biological target.

• It Relies on finding new medication based on the knowledge of the target. Also known as
DIRECT DRUG DESIGN.
Methods used to identify drug targets:

• Biological target identification and validation are among the most important steps in
developing a new drug.
• It is either identified through:
Experimental method Computational method
X-ray crystallography. Genomics
NMR techniques. Proteomics.
Homology modeling. Comparative modeling
Molecular modeling.
STEPS INVOLVED IN STRUCTURE BASED DRUG DESIGN (SBDD)

• Identification of binding site by determining ligand bound 3D structure.

• Virtual screening of large collections of chemical compounds.
• Screening enables the identification of potential new drugs by performing
docking experiment of this collection of molecules.
• a group of molecules with similar docking scores is generally used for
potency determination; this is High-Throughput Screening (HTS).
• After the determination of biological potency, several properties such as
QSAR, QSPR, between potency and docking scores can be determined to
ascertain the potential molecule(s) for lead drug discovery
Molecular modeling:

• Molecular modelling encompasses all methods, theoretical and computational, used to

model or mimic and study the structure and behavior of molecules.
• It uses sophisticated computer programs that can determine the structures and properties
of molecules of interest and then intelligently analyze the data to predict the structure of
an ideal drug candidate
Methods for molecular modeling:

Docking:
• Docking predicts the orientation of small protein molecules or ligands with their target or
receptor.
• It is used to identify and optimize drug candidates by examining and modeling molecular
interactions between ligands and target macromolecules.
Inverse Docking:
It is a computational docking program in which a specific small molecule of interest is tested
against a library of receptor structures.
 VARIOUS TECHNIQUES FOR DRUG DESIGN

• Random screening
Entire synthesized compound or any chemical constituent are evaluated for
biologically active compound. It may produce many active medicines.
Example: many antibiotics, streptomycin, cyclosporine are formed.
• Non-random screening
In this only compound resemble in structural skeleton with each other are evaluated.
• Pharmacokinetic study
In this, bio transformed products are studied for there properties to assess activity
in compound and comparison from its parent compound.
• Pharmacodynamics study:
Side effects in this study may lead to find out a new molecule which come with
appreciable structural modifications. For example; sulfonamide used for typhoid
can cause decrease blood sugar level drastically. This may lead to develop of aryl
sulfonyl urea cause lowing of blood glucose level.
• Drug design through disjunction:
It is the systematic method for formulation of drug analogues. It yield structurally simpler
compounds from parent compound. Various steps are;
- Unjoining of certain bonds
- Substitution of aromatic cyclic system for saturated bonds.
- Elimination of size of hydrocarbon position.
- De-cyclization of any ring system
Techniques:

phenotypic screening.
slicotechniques.