COMPUTERAIDEDDRUGDESIGN 1

COMPUTER AIED DRUG DESIGN

Dissertation Submitted To The

KAVAYITRI BAHINABAI CHAUDHARI
NORTH MAHARASHTRA UNIVERSITY, JALGAON (M.S.)

FOR THE PARTIAL FULFILLMENT OF THE DEGREE OF

BACHELOR OF PHARMACY

Marathe Latikesh Subhash

Marathe Hemant Nivrutti

UNDERGUIDANCEOF

Mr.Nilesh R. Sisode

Asst.Professor
Department of Pharmaceutics

DCS’sA.R.A.COLLEGE OF PHARMACY, NAGAON,DHULE,424005(M.S.)

DCSsA.R.ACOLLEGE OFPHARMACY,NAGAON,DHULE
j

2021-22

CERTIFICATE BY PRINCIPAL

This is to certify that this project entitled, “Computer Aided

Drug Design ” is a bonafied and genuine project work carried

out by Marathe Latikesh Subhash and Marathe Hemant

Nivrutti of Final Year. B. Pharmacy, at DCS’s A.R.A. College of

Pharmacy under the guidance & supervision of Mr.

Nilesh.R.Sisode.

Place: Dhule

Date:

Dr. Rajendra .D.Wagh

Principal
DCS’s A.R.A. College of
Pharmacy, Nagaon,
Dhule

DCSsA.R.ACOLLEGE OFPHARMACY,NAGAON,DHULE
 COMPUTERAIDEDDRUGDESIGN 2

DECLARATION BY THE CANDIDATE

I hereby declare that the matterin the dissertation entitled

“COMPUTER AIDED DRUG DESIGN” is a bonafied and genuine
research work carried out by me under the guidance of
Mr.N.R.Sisode Assistant Professor, Department of Pharmaceutics
DCS’s A. R. A. College of Pharmacy, Nagaon, Dhule.

Date: / /2021
Place:Dhule Marathe Latikesh Subhash
Marathe Hemant Nivrutti
 COMPUTERAIDEDDRUGDESIGN 3

DECLARATION BY GUIDANCE

I Mr. N. R. Sisode hereby declare that the matter in the

dissertation entitled “COMPUTER AIED DRUG DESING” is a
bonafied and genuine research work carried out of under the my
guidance. Department of Pharmaceutics DCS’s A.R.A College of
Pharmacy, Nagaon, Dhule.

Date: / /2021

Place: Dhule Mr.N. R. Sisode

 COMPUTERAIDEDDRUGDESIGN 4

ACKNOWLEDGEMENT

It is with pleasure of immense gratitude that I express my cordial

andhumble thanks to my esteemed guide Mr.Nilesh R Sisode sir
Department of Pharmaceutics D.C.S.’s A.R.A. College of
Pharmacy ,Nagaon, Dhule for offering me his valuable advice ,patiently
supervising me and guiding me in the right direction, keen interest and
perennial inspiration and ever lasting encouragement .I have made lots of
intolerable mistakes during my thesis work but instead of shouting
hetreated me well and advised. I shall forever remain indebted to him
forhaving inculcated in me a quest for excellence a spirit of diligence,
asense of humility, honesty and respect for the moral and ethics
whichgovern our sciences and without whom this work would not have
seen the light of the day.

Besides this several people have knowingly and unknowingly helped me

In the successful completion of the project. I thank all those people…

Thank you all…..!

 COMPUTERAIDEDDRUGDESIGN 5

INDEX
1. ABSTRACT

2.DRUG DESIGN

3.BACKGROUND
4.DRUGDESIGNTYPE
5.COMPUTER AIDED DRUG DESIGN
6.OBJECTIVE
7.DRUGDISCOVERY
8.COMPUTATIONALTOOLS
9.APPLICATION
10.ADVANTAGES & DISADVANTAGES
 COMPUTERAIDEDDRUGDESIGN 6

 ABSTRACT

Computer-aided drug design (CADD)comprises

a broad range of theoretical and computational
approaches that are part ofmodern drug
discovery. CADD methods havemade key
contributions to the development of drugs that
are in clinical use or in clinical trials. Such
methods have emerged andevolved along with
experimental approachesused in drug design. In
this chapter wediscuss the major CADD methods
andexamples of recent applications to drugs
thathave advanced in clinical trials or that
havebeen approved for clinical use. We also
commenton representative trends in current
drug discovery that are shaping the
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development of novel methods, such

ascomputer-aided drug repurposing.
Similarlywe present emerging concepts
andtechnologies in molecular modeling
andchemo informatics. Furthermore, this
chapter discusses the authors’ point of view of
thechallenges of traditional and novel
CADDmethods to increase their positive impact
indrugdiscovery.
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DRUG DESIGN

 INTRODUCTION
Drug design, sometimes referred to as rational
drugdesign or more simply rational design, is the
inventiveprocess of finding new medications based on
theknowledge of a biological target. The drug is
mostcommonly an organic small molecule that activates
orinhibits the function of a biomolecule such as aprotein,
which in turn results in a therapeutic benefitto the
patient. In The most basic sense, drug designinvolves the
design of small molecules that are Complementary in
shape and charge to the bimolecular target with which
they interact and therefore will bind to it.Drug design
frequently but
 COMPUTERAIDEDDRUGDESIGN 9

not necessarily relies on computer Modeling

techniques.

This type of modeling is often referred to ascomputer-

aided drug Design. Finally, drug designthat relies on
the knowledge of the three-dimensional structure of the
bimolecular targetis known as structure-based drug
design.The phrase “drug design” is to some extent a
misnomer. What is really meant by drug design is ligand
design (i.e., design of a small molecule that will bind
tightly to its target).
Although Modeling techniques for prediction of binding
affinity are reasonably successful, there aremany Other
properties, such as bioavailability,metabolic half-life, lack
of side effects, etc., that first Must be optimized before
aligand can become as efficacious drug.

COMPUTERAIDEDDRUGDESIGN 10
 Background
Typically a drug target is a key molecule Involved in
aParticular metabolic or signaling pathway that isspecific
to a disease condition or pathology or To theinfectivity or
survival of a microbial pathogen. Someapproaches
attempt to inhibit the Functioning of thepathway in the
diseased state by causing a keymolecule to stop
functioning. Drugs may be designedthat bind to the active
region and inhibit this keymolecule. Another Approach
may be to enhance thenormal pathway by promoting
specific molecules inthe normal Pathways that may have
been affected inthe diseased state. In addition, these
drugs should alsobedesignedsoasnottoaffect
anyotherimportant
 COMPUTERAIDEDDRUGDESIGN 11

“off-target”moleculesor antiTargetsthatmaybe
similarin appearancetothetargetmolecule.

Since drug interactions with Off-target molecules

maylead to undesirable side effects. Sequence homology
isoften used to identify such risks. Most commonly,drugs
are organic small molecules produced throughchemical
synthesis, but Biopolymer-based drugs (alsoknown as
biologics) produced through
biologicalprocessesarebecoming
increasinglymorecommon.Inaddition,mRNA-
basedgenesilencingtechnologiesmayhavetherapeuticappli
cations.

Therearetwomajortypesofdrugdesign.Thefirstisreferred
to as ligand-based drug design And thesecond,structure-
baseddrugdesign.
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 TYPES
1. ligand-baseddrugdesign

2. structure-baseddrugdesign
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 Ligand-based

Ligand-based drug design (or indirect drugdesign)

relies on knowledge of other
moleculesthatbindtothebiologicaltargetofinterest.Th
eseother molecules may be used to derive
aPharmacophore model that defines the
minimumnecessary structural characteristics a
moleculemust possess in order to bind to the target.
Inother words, a model of the biological target
maybe built based on the knowledge of what binds
toit, and this model in turn may be used to
Designnew molecular entities that interact with
thetarget.
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Alternatively, a Quantitative Structure-

ActivityRelationship (QSAR), in which a
correlationbetween calculated properties of
molecules andtheir experimentally determined
biologicalactivity,maybederived.TheseQSAR
relationshipsin turn may be used to predict the
activity of newanalogs.
 Structure-based

Structure-based drug design (or direct drug design)relies

on knowledge of the three Dimensionalstructure of the
biological target obtained throughmethods such as x-ray
Crystallography or NMRspectroscopy. If an experimental
structure of a targetis not available, it May be possible to
create ahomology model of the target based on
theexperimental structure of a related protein. Using
thestructureofthebiologicaltarget,candidatedrugsthat
 COMPUTERAIDEDDRUGDESIGN 15

arepredictedto bindwithhighaffinityandselectivityto the

target may be designed using
interactiveGraphicsandtheintuitionofamedicinalchemist.
Alternatively various automated
computationalProcedures may be used to suggest new
drugcandidates. As experimental methods such as X-
raycrystallography and NMR develop, the amount
ofInformation concerning 3D structures of
bimoleculartargets has increased dramatically. In
Parallel,information about the structural dynamics
andelectronic properties about ligands has also
increased.This has encouraged the rapid development of
thestructure-based drug design. Current methods
forstructure-based drug design can be divided
roughlyintotwocategories.Thefirstcategoryisabout.
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“Finding”ligandsforagivenreceptor,whichisusuallyreferredasDa
tabasesearching.
 COMPUTERAIDEDDRUGDESIGN 17

FlowchartofaUsualClustering
AnalysisforStructure-BasedDrugDesign.

 Activesite identification

Active site identification is the first step in thisprogram.

It analyzes the protein to find the bindingPocket, derives
key interaction sites within thebinding pocket, and then
prepares the necessary Datafor Ligand fragment link. The
basic inputs for this stepare the 3D structure of the
protein And a pre-dockedligand in PDB format, as well as
their atomicproperties.

Bothligandand proteinatomsneedto beclassifiedand their

atomic properties should be defined,basically,intofour
atomictypes:
 COMPUTERAIDEDDRUGDESIGN 18

(1) Hydrophobic atom: All carbons

inhydrocarbonchainsorinaromaticgroups.
(2) H-bond donor: Oxygen and nitrogen
atomsbondedtohydrogenatom(s).

(3) H-bond acceptor:Oxygen and sp2 or

sphybridizednitrogenatomswithloneelectronpair(s).

(4) Polar atom:Oxygen and nitrogen atoms thatare

neither H-bond donor nor H-bond
acceptor,sulfur,phosphorus, halogen, metal, and carbon
atoms bondedto hetero-atom(s). The space inside the
ligand bindingregion would be studied with virtual probe
atoms ofthe four types above so the chemical
environment ofall spots in the ligand binding region can
be known.Hence we are clear what kind of chemical
fragmentscan be put into their corresponding spots in the
ligandbindingregionof thereceptor.
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 Ligandfragmentlink

Flowchartforstructure-baseddrugdesign
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When we want to plant “seeds” into different

regionsdefinedbytheprevioussection,weneedafragments
databasetochoose fragmentsfrom.Theterm
“fragment”isusedheretodescribethebuildingblocksused in
the construction process. The rationale of this algorithm
lies in the fact that organic structures
canbe decomposed into basic chemical fragments.
Although the diversity of organic structures is infinite,the
number of basic fragments is rather limited. Before the
first fragment, i.e. the seed, is put into the binding pocket,
and other fragments can be added one by one,it is useful
to identify potential problems. First, thepossibility for the
fragment combinations is huge. Asmall perturbation of
the previous fragment conformation would cause great
difference in the following construction process. At the
same time, inorder to find the lowest binding energy on
the Potential energy surface (PES) between planted
 COMPUTERAIDEDDRUGDESIGN 21

Fragments and receptor pocket, the scoring function

calculation would be done for every step of conformation
change of the fragments derived fromevery type of
possible fragments combination. Sincethis requires a
large amount of computation, one may think using other
possible strategies to let the program works more
efficiently. When a ligand is inserted into the pocket site
of a receptor, conformation favor for these groups on the
ligand that can bind tightly with receptor should be taken
priority. Therefore it allows us to put several seeds atthe
same time into the regions that have significant
interactions with the seeds and adjust their favorite
conformation first, and then connect those seeds into a
continuous ligand in a manner that make the rest part of
the ligand having the lowest energy.
 COMPUTERAIDEDDRUGDESIGN 22

The conformations of the pre-placed seeds ensuring the

binding affinity decide the manner that ligand would be
grown. This strategy reduces calculation burden for the
fragment construction efficiently. Onthe other hand, it
reduces the possibility of the combination of fragments,
which reduces the numberof possible ligands that can be
derived from the program. These two strategies above
are well used inmost structure-based drug design
programs. They are described as“Grow”and“Link”.The
two strategies are always combined in order to make the
construction result more reliable.
 COMPUTERAIDEDDRUGDESIGN 23

 Examples
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. Computer-
aided drug design in particular becomes much more
tractable whenthere’s a high-resolution structure of a
target protein bound to a potent ligand. This
approach to Drug discovery is sometimes referred to
asstructure-based drug design. The first unequivocal
Example of the application of structure- based drug
design leading to an approved drug is theCarbonic
anhydrase inhibitor dorzolamide, which was
approved in 1995.Another important casestudy in
rational drug design is imagine, a tyrosine kinase
inhibitor Designed specifically for the
 COMPUTERAIDEDDRUGDESIGN 24

Bcr-abl fusion protein that is characteristic for

Philadelphia Chromosome-positive
leukemia’s(chronic myelogenous leukemia and
occasionally acute Lymphocytic leukemia). Imatinib
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. Additional
examples include:

o Many of the atypical antipsychotics

o Cimetidine, the prototypical H2-receptor
antagonist from which the later members of
the Class were developed
o Selective COX-2 inhibitorNSAIDs
o Dorzolamide, a carbonic an hydrase inhibitor
used to treat glaucoma.
o Enfuvirtide, apeptide HIV entry inhibitor
 COMPUTERAIDEDDRUGDESIGN 25

o No benzodiazepines like zolpidem

andzopiclone
o Probenecid
o SSRIs (selective serotonin reuptake
inhibitors),a class of antidepressants

o Zanamivir,anantiviraldrug

o Inertness,HIV Integrate inhibitor

 COMPUTERAIDEDDRUGDESIGN 26

 COMPUTER-AIDEDDRUGDESIGN

 INTRODUCTION

Although the phrase computer-aided drug design

may seem to imply that drug

Discovery lies in the hands of the

computational scientists who are able to
manipulate

Molecules on their computer screens, the drug design

process is actually a complex and
Interactive one, involving scientists from many
disciplines working together to provide many
 COMPUTERAIDEDDRUGDESIGN 27

Types of information.The modern computational and

experimental techniques that have

Been developed in recent years can be used

together to provide structural information

About the biologically active molecules that are

involved in disease processes and in Modulating
disease processes.
 COMPUTERAIDEDDRUGDESIGN 28

 OBJECTIVE
change from:-
 Random screening against disease assay
 Natural product, synthetic chemicals
 Rational drug design and testing
 Speed upscreening process
 Efficient screening
 Denovo design
 Fails drugs fast
 COMPUTERAIDEDDRUGDESIGN 29

 DRUGS DISCOVERY

Occasionally new drugs are found by accident. More

frequently they are developed as part

Of an organized effort to discover new ways to

treat specific diseases.The discovery of new

Pharmaceutical agents has gone through an

evolution over the years and has been adding

New technologies to this increasingly complex

process.
 COMPUTERAIDEDDRUGDESIGN 30

 Screening for new drugs

The traditional way to discover new drugs has

been to screen a large number of

Synthetic chemical compounds or natural products

for desirable effects. Although this

Approach for the development of new

pharmaceutical agents has been successful in the

Past, it is not an ideal one for a number of reasons.

The biggest drawback to the screening process is

the requirement for an appropriate
 COMPUTERAIDEDDRUGDESIGN 31

Screening procedure. Although drugs are ultimately

developed in the clinic,it is usually

In appropriate to put chemicals of unknown

efficacy directly in to humans.Consequently,

Other systems have to be developed. Normally a

battery of screens is used to select

Potential new drug candidates, with activity ininitial,

rough screens feeding compounds into

Later,more sophisticated screens.Initial screens are

often in vitro tests for some fundamental activity,
such as the ability to kill bacteria
insolution.Ultimately,however,
More applicable in vivo screens are needed. This
second level of screening is normally
 COMPUTERAIDEDDRUGDESIGN 32

Carried out using animal model systems for the

disease.
Screens have in here limitations
. Primary screens are used for large number of
Chemicals to choose which compounds should be
further tested with more sophisticated
Tests. If the primary screen does not select for an
appropriate activity,however,anactive
Structure will appear obeinactive and will notbe
discovered. Secondary screening in
Animal model systems has additional
problems,such as
1. The animal model may not accurately reflect the
human disease
2. The chemical may be extensively metabolized
to a different compound in the animal
Before It reaches its target
 COMPUTERAIDEDDRUGDESIGN 33

3. The chemical may not be absorbed or

distributed as it is in humans.
In each of these cases, the active structure potentially
will not be identified.
Another serious problem with the screening
process is that, because of its random nature,
It is inherently repetitious and time-consuming
just to find a chemical with the desired Activity.
Further more, chemical compounds discovered by
this approach commonly do not have
Optimal structures for modulating the biological process.
This in turn may require
Administration of larger quantities of the drug
andincrease the risk of unwantedside
Effects. The major advantage of screening is the
larger amount of information that is not
 COMPUTERAIDEDDRUGDESIGN 34

needed to carry out the process. One does notneed

to know the structure of the drug being Sought. Nor
does one need to know the structure of the target
upon whichthedrug will act.
Most importantly, one does not need to know
about the underlying mechanism of the Disease
process itself.
 COMPUTERAIDEDDRUGDESIGN 35

 Modifications for improvements

Once an active (lead) compound has been

identified and its chemical structure

Determined,it is usually possible to improve on

this activity and/or to reduce side effects by

Making modifications to the basic chemical

structure.Modifications to improve performance

Are often carried out using chemical or bio

fermentative means to make changes in the lead

Structure or its intermediates .Alternatively, for

some natural products, the gene itself may
 COMPUTERAIDEDDRUGDESIGN 36

Be engineered so that the producer organism

synthesizes the modified compound directly. The
process of developing drugs via modification of
active lead compounds requires The structure ofthe
compound to be known. One still does not need to
know the structure of The target on which
 COMPUTERAIDEDDRUGDESIGN 37

The drug works. Likewise, no information about

the underlying disease Process is required

As with screening, the process of modification is

often based on a primarily trial-and-error

Approach. Because more information is

known,however,this process can be carried out

With much greater probability of success than a

purely random process. A prime example of

The power of this approach is in the anti-infective

area where modifications of the original

First generation cephalosporin’s have led to

Second and now third generation offspring with
 COMPUTERAIDEDDRUGDESIGN 38

Substantially improved characteristics.

Thelimitations of this process are in herent to the
fact Compound as the basis for further drug design.
Improvements are likely however, no major Break
through in developing new chemical entities(NCEs) is
probable. Further, if the original Lead compound fails
to generate a desirable Finding a new lead molecule.
COMPUTERAIDEDDRUGDESIGN 39
 COMPUTERAIDEDDRUGDESIGN 40

 Computational tools for drug

designing

 Database and draw tools

 Molecular modelling and Homology
modelling
 Binding site prediction and docking
 Ligand designing screening-QSAR
 Binding free energy estimation
 ADME toxicity
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 Database:-
o Zincdatabase
o C h embl
o JchemforExcel
o ProteindataBank
o Bindingmoad
o PDBBind
 COMPUTERAIDEDDRUGDESIGN 42

 Drawtools:-
o Chemdraw
o Marvinsketch
o Chemsketch
o Marvinmolecule editor
o Chemwriter.
 COMPUTERAIDEDDRUGDESIGN 43

 Molecularmodelling :-
o CHARMM
o GROMACS
o AMBER
o SWISSPARAM
o CHARMM.org
o CHARMM-GUI
 COMPUTERAIDEDDRUGDESIGN 44

 APPLICATION
 COMPUTERAIDEDDRUGDESIGN 45

DCSsA.R.ACOLLEGEOFPHARMACY,NAGAON,DHULE
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