Complete knowledge of structure based drug designing

1. STRUCTURE BASED DRUG DESI
GNING
GROUP NO.6

2. What is Drug?
Drug is an organic small molecule design to
bind, interact, and modulate the activity of
specific biological receptors.

3. Drug Designing
Drug design, often referred to as ration
al drugdesign or simply rational design,
is the inventive process of finding new m
edications based on the knowledge of a b
iological target.

4. Aims of Drug Design
Relation of
chemical
structure to
biological
activity.
Conduction of
structure
activity analysis
Prediction of
given molecule
bind to target .

5. STRUCTURE-BASED DRUG
DESIGN.
DEFINITION:
"It is the design and modification of a chemical str
ucture with the aim of identifying a compound suit
able for clinical testing, basically a drug candidat
e in medicinal chemistry studies”.
DESCRIPTION:
It is one of the first techniques to be used in drug design.
It has helped in the discovery process of new drugs.

6. METHODS:
1. Ligand based Drug Design Or Database Se
arching:
The first category is about “finding” ligands f
or a given receptor, which is usually referred
as database searching.
2. Receptor based Drug Design:
Second category is about “building” ligands,
which is usually referred as receptor- based
drug design.

7. STRUCTURE BASE DRUG DE
SIGN PROCESS

8. DOCKING
• In the field of molecular modelin
g docking is a method which pre
dicts the preferred orientation o
f one molecule to a second when
bound to each other to form a st
able complex.
• Molecular docking is one of the
most frequently used methods in
structure based -designing due
to its ability to predict the bindi
ng-conformation of small molecu
le ligands to the appropriate tar
get binding site.

9. DOCKING METHADOLOGIES:
1.Rigid ligand and rigid receptor docking
When the ligand and receptor are both treated as ri
gid bodies, the search space is very limited, considerin
g only three translational and three rotational degree
s of freedom
2.Flexible ligand and rigid receptor docking
In that case both the ligand and receptor change th
eir conformations to form a minimum energy perfect-f
it complex. Thus the common approach, also a trade-of
f between accuracy and computational time, is treatin
g the ligand as flexible while the receptor is kept rigid
during docking.

10. 3. Utilizing rotamer libraries
Rotamer libraries include a set of side-chain
conformations which are usually determined
from statistical analysis of structural experi
mental data.
4. AutoDock
Adopt a simultaneous sample method to de
al with side chain flexibility. Several side ch
ains of the receptor can be selected by users
and simultaneously sampled with a ligand us
ing the same methods.

11. Theory of docking
Essentially, the aim of molecular docking is to give a pr
ediction of the ligand-receptor complex structure using
computation methods. Docking can be achieved throug
h two interrelated steps: first by sampling conformatio
ns of the ligand in the active site of the protein; then ra
nking these conformations via a scoring function.

12. SCORING
Each solution should be tested during structural
based drug designing to decide which is the most
promising, this is called as scoring.

13. SCORING TYPES
• FORCE FIELD SCORING:
Force fields are mainly used to compute the inte
raction energy between the protein and the ligan
d.
• EMPERICAL SCORING:
It is based on the descriptors that describe the b
inding event.
• KNOWLEDGE BASED SCORING:
It is based on the statistical analysis of interacti
ng atom pairs from protein–ligand complexes.

14. APPLICATION OF DOCKI
NG
Hit
identification
lead
optimization
Bioremediation
Used to predict pollutants that can be degraded
by enzymes
docking with a scoring function can be used to
quickly screen large databases of potential
drugs in silico to identify molecules that are
likely to bind to protein target of interest
Used to predict in where and in which relative
orientation a ligand binds to a protein.

15. USES OF DOCKING
 Drug target
 Protein ligand interactions
 Better understand the machinery of life
 Enzyme-inhibitor class
 Antibody-antigen class
 Protein therapies
 Engineered protein enzymes

16. DE NOVO DRUG DESIGN
 De novo means starting from the scratch or fresh,
or from very beginning.
 PRINCIPLE:
• Assemble possible compound and evaluate their
quality.
• Searching sample space from novel structure wi
th drug like properties

18. SUCCESSFUL CONTRIBUTIONS OF
SBDD
 Example of application of SBDD was the
design of HIV-I protease inhibitor.
 It is made up of 2 halves. It looks like a
butterfly.
 Normally in symmetric molecules, both
halves have active sites to carry enzyme
job but in HIV-I protease, only one activ
e site is present in the center of both hal
ves.
 By the help of SBDD, his active site is pl
ugged by a small molecule so that the en
zyme is shut down and stop the virus sp
read in the body.

19. EXAMPLES OF SBDD
 Ritonavir is one of a class of anti-HIV drugs, whic
h is a protease inhibitor.
 Indinavir is another example of very potent pepti
domimetic compound discovered using the eleme
nts of 3D structure and Structure Activity Relati
onship.