124

Compuler Aided Drug Design

Structure Scarching involves in determination of features like bond orders, ri
the whole structure, substructure, Stri ture
and aromaticity. It includes searching
builds on information obtained from varie
similarity and diversity. CASE arious
like IR, NMR, MS, Structure etc. Descriptor used
spectroscopic methods
identify the physical chemical and biological properties of chemical compotd
and relationship between two structures.

The descriptors fall into four classes such as:

Topological
2) Geometrical,
3) Electronic, and
4) Hyhrid or 3-D Descriptors.

Structure
Chemmetrics
Descriptors

Property Prediction

Figure 7.7: Structure Representation and

Chemmetrics
3) Chemmetrics: Chemmetrics is used for quantitative analyse of the chemical
data by using mathematical and statistical methods. It also deals with
property prediction of chemical information (Figure 7.7).

7.1.2.6. Applications of Chemoinformatics

The range of applications of Chemoinformatics is rich indeed; any field of
chemistry can profit from its methods. The following lists different areas of
chemistry and indicates some typical applications of chemoinformatics:
1) Storing data generated through experiments or from molecular simulation
Retrieval of chemical Structures from chemical database (Software libraries).
2) Prediction of physical, chemical and biological properties of chemical
Compounds.
3) Elucidation of the structure of a compound based on spectroscopic data.
4) Structure, Substructure, Similarity and diversity searching from chemical
database
5) High Throughput Screening (HTS) is the integration of technologi
(laboratory automation, assay technology, micro plate based instrumentation.
etc.) to quickly screen chemical compounds in search of a desired activity
6) Docking-Interaction between two macromolecules.
7) Drug Discovery.
8) Molecular Science, Materials Science, Food Science (nutraceuticals t r a c e u t i c a l s ) .

Atmospheric Chemistry, Polymer chemistry, Textile Industry, Combinatorial

organic synthesis (COS).

 Computer Aided
130 Drug
Design
Semi-empirical, ab initio quantum chemistry
methods, or
densitydensity unciona
optimised parameters for the molecular
for
theory are often used to provide the
electroFni
estimate or
mechanics calculations and also provide an
(electrostatic potential, polarisability, etc.)
influence binding affinity.
of the drug candidatepen
andidate that wil
also be used to provide semie
Molecular mechanics methods may
Also, knowledge-based scoring functantitat
prediction of the binding affinity. estimates. These methods use linear mayh
used to provide binding affinity
nets or other statistical techniques to deriveession
machine learning, neural
experimental affinities to comn. ve
binding affinity equations by fittingthe small molecule and the
derived interaction energies
between target computationally
the help of computers may be used at any of the 6.
Drug design with following
stages of drug discovery:
using screening (structure- or ligand-based des:.
virtual
1)
2)
Hit identification
Hit-to-lead optimisation of affinity and selectivity (str jesiga)
(structure-based
design. QSAR, etc.).
3) Lead optimisation of other pharmaceutical properties while maintain
ning
affinity.

7.2. DATABASES
Healthcare databases are systems into which healthcare providers routinely enter
clinical and laboratory data. One of the most commonly used forms of healthcare
databases are electronic health records (EHRs). Practitioners enter routine
clinical and laboratory data into EHRs during usual practice as a record of the
care. Other healthcare databases include claims databases,
which are
patient's
maintained by payers for reimbursement purposes, pharmacist databases and
for the
patient registries. Healthcare databases can be used as data sources in
of real-world evidence Three
(RWE). of databases are
types used
generation
informatics:
1) ADME Databases
2) Chemical Databases
3) Biochemical Databases
4) Pharmaceutical Databases

7.2.1. ADME Databases

Usually Drug Absorption, Distribution, Metabolism and Excretion (ADin
the interaction of a drug with particular ligands/proteins. The progress and
of pharmacokinetics prediction tools, molecular mechanism of dispb
individual response and therapeutic action of drugs can be studied eas
having the information about these ADME-linked proteins.
garding

The ADME Database comprises of updated

interactions of substances with Drug Metabolising Enzymes m c
and complete dataand
Enzymes Dru8

rch and developmen

Transporters. It has been proposed for the use of drug research and
 Methods in Drug Design (Chapter 7)
131

u e nn volves es the studyy of drug-drug interactions and ADME. The information

category (therapeutic area), drug name, enzyme, reaction and the
tn mical/metabolite structures and the kinetic values stated in the
lhe this database (Figure 7.8).
M e r a l u r es u

ports
p p

/scd on
ci ginal Human Pas0 and Transporter Metabolism Database the
ori

o f this database are collected and organised. The database can be

S S e d nline Onlir and can be searched by using the keywords or chemical
CuAlso
irileu r e .
Al the advanced searches can be done for the investigational
dics zarding drug-
g-drug interactions. There are more than 26,000
e s in ADME Database which includes several natural products and
hstanpreparations, adding to the other factors effecting Drug
s u b s l a .

theeing Enzymes activity. More than 18,000 citations were used to

l l e c tt h e data

res of Human Drug Metabolising Enzyme Database

fealu
aaformation
information about CYP enzymes (Cytochrome Paso) and numerous
The
unts that are tested in the metabolism of xenobiotic and endobiotics in
ans are present in this database. It also contains the information regardings
ihstances affecting CYP activity that rely on interactions with substrate,
ubs
inducer and activator.
ahibitor,
nformation regarding other information like Esterases, UDP-
enzymes
gucuronosyl transferases, Sulphotransferases, Glutathione S-transferases, Flavin
containing Monooxygenases is also mentioned in this database.

Kinetics
information

Human
drug metabolising References
enzyme

Compound Human
Structure Transporteer

Figure 7.8: ADME Database

hetics Information Database

Database are
nrting entries for the Human Drug Metabolising Enzyme
in this databas a s e which provides
numerical data on major kinetic
aTameters
omas nat are relevant for the study of drug development/application.
mation garding in vitro assay used Km max Kj, K_inactivation,
The

oper"perativityn, 1C I50, ECso, t1/2 are found in this

database. When the kinetic
aabase
en is
itit ines with the Human Drug Metabolising Enzyme
Database only

accessible.
132 mputer Aided
Drug Delipn
gn
Human Drug Transporter Database
The information about transporters present in drug ransport, phve
compounds, nutrients and other chemicals and
metabolites are
hysiological
found in this
database. It also includes ABC Transporters, Organic lon Transp

Transporters, Nucleotide Transporters, etc.

Transporters, Peptide
Numerous databases having the descriptions regarding particular ca
ADME- associated proteins have been introduced in addition to esof
mentioned database. To provide complete information regarding all the above
ADME-associated proteins along with the physiological functionses of
function of
directic each
ligand/protein, ADME classification, pharmacokinetic effect, direc
driving force of disposition, location and tissue distribution, sn.
substrates, gene name as well as protein availability in other speci ms
es a new
database i.e. ADME-associated proteins (ADME-AP) is introduced.

For accessing information about the sequence, function, 3D structure,

genetic
disorders, polymorphisms, nomenclature, ligand binding properties and relad
literatures of each protein, the cross links to other databases is also available in
this database. At present time ADME-AP includes 321 proteins and 9
substrates.

7.2.2. Chemical Databases

A chemical database is a database which is particularly designed for storing the
chemical information. All the information related to the chemical (such as crystal
structures, spectra, synthesis, reactions and thermo-physical data) are found in
this database. No matter a chemical database is chemo-informatics or
bioinformatics, atill it is said to be the backbone of computer aided dnug
discovery. The information in these databases can be useful in building
knowledge based models for discovering and designing drug molecules.

Following types of chemical database are used:

1) Chemical Structure Database: Generally, the Chemical structures are
represented with the help of lines which indicates the chemical bonds
between atoms and 2D structure drawn on paper. For the chemist, they can
be perfect visual representations, but not for computational use and
especially for search and storage. The lists of atoms and their connections ane
Used for representing small molecules of ligands. However, large molecules
like proteins can be represented more of
proficiently by using the sequene
their amino acid building blocks. can

Large chemical structure datain

store and search the information taking
regarding millions of molecules
terabytes of physical memory.

Chemical structures are represented

by following ques:

i) In a form of connection
two principal tec iding
additional information about tables/adjacency matrices/ists ades).
bond (edges) and atom
for example, MDL, Molfile, CML, PDB.
attributes
breadth
ii) In a form of a linear string notation on the basis of
first traversal, for example SLN, WLN, SMILES/SMARTS,depth first Chl.
taformatics and Methods in Drug Design (Chapter 7) 133

These approaches have been introduced for

of allowing the representation
stereo-chemical differences and charges, and also for special types of
bonding which are present in organ0-metallic compounds. Better storage
as well as fast
and flexible search is the main advantage of a computer
representation.
2) Literature Database: They are used for correlating the structures or other
chemical information with significant references like research
papers
patents. Scifinder, STN and Reaxys are example of this database. o For
focusing on chemical characterisation the associations with literature are also
found in many databases.
3) Crystallographic Database: This database includes X-ray crystal structure
data. Protein Data Bank and Cambridge Structural Database are some
common examples.
4) NMR Spectra Database: It is used to link chemical structure with NMR
data. Generally, other characterisation data like FTIR and mass
spectrometry
are also present in these databases.
5) Reactions Database: Mostly information regarding stable molecules is
present in chemical databases. On the other hand the reactions database
includes the information about the intermediates and temporarily produced
unstable molecules. It also contains information of products educts and
reaction mechanisms.
6) Thermophysical Database: It contains information regarding phase
equilibria along with the solubility of gases in liquids, vapour-liquid
equilibrium, liquids in solids (SLE), vaporisation heats of mixing. and
fusion. Caloric data (like heat of formation, heat capacity, combustion) and
transport properties (like viscosity and thermal conductivity) are also
present in this database.

Various free databases available for chemical structure search are as follows:
) PubChem: This database was introduced in 2004 which contains the
information about the biological activities of small molecules. In the NCBI's
Entrezinfomation retrieval system it is organised as three linked databases
i.e., PubChem Substance, PubChem Compound, and PubChem Bio Assay.

A fast chemical structure similarity search tool is also offered by PubChem.

The links present in the homepage can be used to find out more information
database. The information about
regarding the use of each component of PubChem's chemical
can be found by the Relations
biological properties
structure database records to other
Entrez databases.
2) ChemSpider: It is a free chemical structure database which otfers fast text
28 million structures from hundreds of
and structure search access to over

data sources.
ChemFrog: It chemical database that offers information about more than
is a
and vendor.
million commercially available chemicals
is most diverse and
ChemDB: It is a IGB Chemical Database that
and application for the public use.
set of Chemoinformatics tool
advantageous
 134 Computer Aided
Drug Desgn
5) iScienceSearch: This internet search engine is usclul tor the chem.
supports mobile devices and the structures can bc casily drawn talo
like an iPad.
on gadgets
6) Chenmicalize: It calculates structure parameters from ChemA
official website i.e.. www.chemicalise.org. hemAxon on its
7) The DistilBio: It is a latest powerful, federated,life sciences search
life sciences seareh
It can instantly display the results at its
http://www.distilbio.com. However, with its immediate search
official websiteengineie
search
auto-complete, the research can be easily found at one place
results
nd

7.2.3. Biochemical Databases

The need for introducing database systems that can support the research activ
have been formerly recognised by biology and biochemistry research
communities. The increasing growth of biochemical data, generated becauyeo
using new high throughput experimental technologies and methods
encouraged the idea of this database. Several data repositories along with
different access mechanisms, formats and structures contain the data allied with
biochemical pathways. It is necessary to assimilate the data in a broad manner in
order to make these data sensible. Some biochemical databases are as follows
1) Pathguide: This database provides the information of about 231 biological
pathway resources.
2) BioCarta: It used to observe genes interaction in dynamic graphical models.
The important resources containing the information or over l20,000 genes
from several species can be collected and summarised by this database.
3) BioSilico: It is a web-based database system that is beneficial for searching
and analysing the metabolic pathways. Heterogeneous metabolic databases
(like ENZYME, LIGAND, EcoCyc and MetaCyc) combines in a systematic
way and permits the users to completely regain information on enzymes
biochemical compounds and reactions.
4) Human Cancer Protein Interaction Network (HCPIN): It is a weo
accessible database which is mainly used by cancer biologists who
interested in determining 3D protein structural information in the context
the protein interaction network.
omprises of gene
5) KEGG: It is a database of biological systems which compri: ilding
building blocks of genes and proteins (KEGG GENES), ehemGAND
blocks of both endogenous and exogenous substances (KEGG LIG (KEGG

molecular wiring diagrams of interaction and reaction newl object

PATHWAY), and hierarchies and relationships of various bIOOliking
(KEGG BRITE). In addition, a reference knowledge base sses o
genomes to biological systems and also to environments by the pro
PATHWAY mapping und BRITE mapping is also found in KE predicted

6) STRNG: This database contains the information of known anctiona

t (tuncti
protein-protein interactions. Both direct (physical) and indirect ion th
ronm the

sociations are involved in these interactions. They can be derive.

Benomic context. c
sources such as high throughput experiments, genomie c
expression and previous knowledge.
 formatics and Methods in Drug Design (Chapter 7)
formatics 135

Unified Human Interactome: It IS a broad database is a computational and

experimental based human protein interaction networks. To incorporate
diverge maps that provide the research, a flexible and direct entry gate into the
human interactome is its main aim. More than 178,000 different interactionss
between over 18,500 unique human proteins are present in its first version.
8) BRENDA: It is the Comprehensive Enzyme Information System also
known as Enzyme database. The scientists (Biology or Chemistry) extract
the data regarding enzyme function directly from the literature.
primary
Formal and consistency checks
are done with the help of
computer
programs and at least one biologist and one chemist manually checks each
data set on a classified enzyme.

7.2.4. Pharmaceutical Databases

The information regarding chemical, pharmacodynamics and
pharmacokinetic
property of the drugs can be found in this database. It is beneficial in the study of
bioinformatics and Chemoinformatics for discovering the most efficient and safe
drug. Some of the drug databases are discussed as followvs:
1) DrugBank: This database is a unique bioinformatics and chemoinformatics
resource. Extensive data on the nomenclature,
ontology, chemistry, structure,
function, action, pharmacology, pharmacokinetics,metabolism
pharmaceutical properties of both small molecule and large molecule drugs
can be found in this database. About 4300
drug entries involving more then
1,000 FDA approved small molecule drugs, 113 FDA
approved biotech
(protein/peptide) drugs, 62 nutraceuticals and more than 3000 experimental
drugs are present in it. In addition more than 6,000 protein (i.e., drug target)
sequences are associated with these drug entries. Every Drug Card entry
covers more than 80 data field having half
information
drug/chemical data and the other half about the drug target or proteinregarding
data.
2) Drugs.com: It is the most trending, broad and updated source of
drug information
online. Correct, free and independent guidance on miore than 24000
prescription
drugs, OTC medicines and natural products is provided in this database.
3) PharmGKB: This database contains the information
regarding the
relationships between drugs, diseases and genes, along with their difference
and genes products.