DRUG DESIGN

Introduction to Drug Design

Various approaches used in drug design.
Physicochemical parameters used in quantitative structure activity relationship (QSAR) such
as partition coefficient, Hammet’s electronic parameter, Tafts steric parameter and Hansch
analysis.
Pharmacophore modelling and docking techniques.
Combinatorial Chemistry: Concept and applications of combinatorial chemistry: solid phase
and solution phase synthesis.

INTRODUCTION
 Drug Design is the important part of the drug discovery. It 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 and or its
physico-chemical properties involved.
 The drug discovery and development are very time and resources consuming process.
Due to the high research & development (R&D) costs and extensive clinical testing,
drug discovery and development has become an expensive process (Avg cost millions
of USDand 10-15 years)

Drug Discovery
Stages With the development of the pharmaceutical world towards the end of 19
Discovery become a highly focused and manages process.
th Century, Drug

Preclinical
Stage 4
Developments
1- 2 Years
Drug Discovery Stage 3
2- 5 Years

Stage 2 Regulatory
Approval
1-2 Years
Stage 1
Clinical
Developments
5 – 7 Years

100 Projects Millions 1 – 2 Molecules

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 Drug Discovery “To discover a effective medicine, select a proper target & lead”

Stage 1 (Drug Design) Target Selection

Select a Defined Target Proteins:
Receptors, Enzymes, Ion Channels
Systemic planning a project to
discover a new drug from a
Lead Findings
unknow or known sources.
- Novel drugs Selection and Finding of Lead
- Me too version compounds: Synthetic/Natural
products
Drug
Discovery
Lead Optimization
Optimize the lead activity on selected
target protein: selectivity, metabolic
stability, potency

 Drug design or rational drug design is the innovative process of finding new drug
molecules based on the knowledge of the biological target.
 The drug is mostly an organic molecule which activates or inhibits the function of
target proteins that in turn results in a therapeutic effect.
 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
hydrogen- bonding
 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.
 Based on the information that is available, one can apply either ligand-based or
structure based drug design methods.
 Regulatory agencies as well as pharmaceutical industry are actively involved in
development of computational tools that will improve effectiveness and efficiency of
drug discovery and development process, decrease use of animals, and increase
predictability.
 There are two major types or approaches to drug design.
o Ligand based drug design (Indirect drug design)

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 o Structure based drug design (Direct drug design)
 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) Q SAR
(B) Analog drug design
(C) Combinatorial chemistry
(D) Natural Products as a lead, etc
 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.

**Pharmacophore: is a group of atoms in the molecule of a drug responsible for the drug's
action

RATIONAL APPROACHES & CONCEPTS

Drug design seeks to explore:
 Effects of biological compounds on the basis of molecular interaction
 Explore the various process involve in drug discovery
 Explore drug-protein interaction to elicit biological response
 Probable relationship between biological activity and chemical structure.
Concept of LEAD
Lead is the prototype bioactive molecule subjected to drug design and drug discovery and needs
to exploration and exploitation.
 Exploration of Lead: The search for new lead.
 Exploitation of Lead: Requires assessment, improvement and extension of lead.
Concept of Analogue
 Chemical Derivatives or structural analogue having similar structure with little
medication
Concepts of Prodrug
 Prodrug is the appropriative derivatives which converts active metabolite invo

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 VARIOUS APPROACHES USED IN DRUG DESIGN
 The various approaches used in drug design (Ligand based or Structural
based)include the following.
1) Drug discovery via Random screening of synthetic compounds or chemicals and
natural products by bioassay procedures.
2) Drug discovery via metabolic studies
3) Drug discovery via Novel compounds preparation based on the known structures of
biologically active, natural substances of plant and animal origin, i.e., lead skeleton.
4) Drug discovery via Preparation of structural analogs of lead with increasing biological
activity and Application of bio isosteric principle.

I. Ligand Based Drug Design

 Ligand based drug design or indirect drug design is an approach used in the absence
ofthe receptor 3D information and it based on knowledge of molecules that bind to the
biological target of interest.
 A model of the biological target may be built based on the knowledge of
o what binds to it ????
o Hydrophobic and hydrophillic groups
 3D quantitative structure activity relationships (3D QSAR) and pharmacophore
modeling are the most important and widely used tools in ligand based drug design.

 **Pharmacophore: is a group of atoms in the molecule of a drug responsible for the

drug's action

 They can provide predictive models suitable for lead identification and optimization
 Basic Approaches:
(A) Q SAR
(B) Analog drug design
(C) Combinatorial chemistry
(D) Natural Products as a lead, etc

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A) 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…..)
Activity = function (xi)
xi- descriptor
Property- geometry, steric, or steric etc
B) 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 theirchemical structure.

N N Cl

CH3 CH3
CH 2CH2CH 2 N
CH2 CH2 CH2 N
CH3 CH3
Imipramine Chlorpromazine
 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:
o Bioisosteric replacement
o Design of rigid analogs

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 o 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
o Alteration of stereochemistry, or design of geometri isomers (or) stereoisomers
o Design of fragments of the lead molecule that contain the pharmacophoric group
(bond disconnection)
o Alteration of interatomic distances within the pharmacophoric group or in other
parts of the molecule
 Bioisosteric replacement strategy has been fruitful in design of psychoactive agents, by
use of the antidepressant dibenzazepine derivative Imipramine as the lead. The
structuralsimilarity between imipramine and the phenothiazine antipsychotics [typified
by chlorpromazine is apparent.

C) 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

D) Natural Product as Lead

 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

II. Structure Based Drug Design

 Structure-based drug design (or direct drug design) relies on knowledge of the three-
dimensional structure of the biological target obtained through methods such as x-ray
crystallography or NMR spectroscopy

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 Structure of COX-2 Ibuprofen

COX-2- Ibuprofen Interaction

 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
desirablepharmacological properties.

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  The prediction of affinity based on the docking score, developed by Böhm to develop
a general-purposed empirical scoring function in order to describe the binding
energy. The following “Master Equation” was derived:

(A) 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
(B) 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.

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QSAR (QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIPS)
 QSAR is a computational modeling method for revealing relationships between
structuralproperties of chemical compounds and biological activities
 Hansch, (1964)- Structural properties of a chemical influence its biological activity
and similar compounds behave similarly.
 So 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…..)
Activity = function (xi)
xi- descriptor
Property (xi)- size, shape, no. of H-bond, electrostatic etc
 Advantages:
o a) we can predict the activity of unknown or new compound
o b) Short list of active compounds
o estimation of physical/chemical property of unknown compounds based on
knowledge of known compounds

 In molecular docking the geometrical structure of both the ligand and the target protein
must be known. But the Quantitative Structure-Activity Relationships (QSAR) is a method
which can be applied regardless of whether the structure is known or not.
 QSAR explore how a given protein interacts with some tested compounds. As an
example, it may be known from previous experiments that the protein under
investigation shows signs of activity against one group of compounds, but not against
another group. In terms of the lock and key metaphor, we do not know what the lock
looks like, but we do know which keys work, and which do not.
 In order to build a QSAR model for deciding why some compounds show sign of
activity and others do not, a set of descriptors are chosen. These are assumed to
influence whether a given compound will succeed or fail in binding to a given target.
The parameters such as molecular weight, molecular volume, electrical and thermo
dynamical properties are usedas descriptors.

 QSAR derive models which describe the structural dependence of biological activities
either by physicochemical parameters (Hansch analysis), by indicator variables
encoding different structural features (Free Wilson analysis), or by three-dimensional
molecular property profiles of the compounds (comparative molecular field

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 analysis, CoMFA).

 QSAR based on Hammett's relationship utilize electronic properties as the descriptorsof

structures.
Descriptor/ Properties/ Features:
 Physico-chemical properties
 Electronic
 Steric
 Lipophilicity
 Hydrogen bonding
 Shape
 Charge
 Polarizability
Activity = function (Descriptors)

Molecular Descriptor Used in QSAR

A) Hydrophobic Parameter
 Partition coefficient; log P
 Hansch’s Substitution Constant; π
 Hydrophobic fragmental constant; f, f’
 Distribution Cofficient; log D
 Solubility parameter; log S
B) Electronic Parameters
 Hammett costant; σ, σ+, σ-
 Taft’s inductive (polar) constant; σ*
 Swain and Lupton field parameter
 Ionization constant; pKa, ∆pKa
C) Steric Parameter
 Taft’s steric parameter; Es
 Molar volume; MV
 Van der waals radius and volume
 Molar refractivity; MR
D) Quantum Chemical Descriptor
 Atomic net charge; Qσ, Q π
 Super Delocalizability
 Energy of highest occupied molecular orbital; EHOMO
 Energy of lowest unoccupied molecular orbital; ELOMO

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 E) Spatial Descriptor
 Jurs descriptor
 Shadow indices
 Radius of Gyration
 Principle moment of inertia

Descriptors based on the dimensionality of their molecular representation

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A) 0-Dimension descriptors
Atom count, bond counts, molecular weight, sum of atomic properties, chemical
Formula
Examples: Molecular weight, average molecular weight number of: atoms, hydrogen atoms
carbon atoms, hetero-atoms, non-hydrogen atoms, double bonds, triple bonds, aromatic bonds,
rotatable bonds, rings, 3 or 4 or 5 or 6 – membered ring,

B) 1-Dimension descriptors: Fragments counts

Examples: Number of: primary C, secondary C, tertiary C, quaternary C, secondary carbon in

ring, tertiary carbon in ring, quaternary carbon in ring, unsubstituted aromatic carbon,
substituted carbon, number of H-bond donar atoms, number of H-bond acceptor atoms,
unsaturation index, hydrophilic factor, molecular refractivity

C) 2-Dimension descriptors: Topological descriptors

Example: Zagreb index, Wiener index, Balaban J index, connectivity indices, chi (x), kappa
(K) shape indices

D) 3-Dimension descriptors: Geometrical descriptors

Example: Radius of gyration, E-state topological parameters, 3D Wiener index, 3D Balaban
index, Surfaces (Van der Waals Surface Area / Solvent-accessible Surface Area / Polar surface
area / lsotropic surface area-Non-specific interactions with the solvent / Hydrophobic —
Hydrophilic surface area)/ Volumes (Solvent-Excluded Volume) Geometrical / Electrostatic /
Charged partial surface areas / HOMO and LUMO Potential energy (Energy differences /
Active conformation — global minimum conformation / Binding energies / lonization potential

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 PHYSICOCHEMICAL PARAMETERS USED QSAR
Partition coefficient, Hammet’s electronic parameter, Tafts steric parameter and Hansch
analysis.
Partition Coefficient (Log P)
 Log P, or octanol-water partition coefficient, is a measure of hydrophilicity and
hydrophobicity of the compounds.
 In the physical sciences, a partition coefficient (P) or distribution coefficient (D) is the
ratio of concentrations of a compound in a mixture of two immiscible
solventsat equilibrium.
 This ratio is therefore a comparison of the solubilities of the solute in these two
liquids. The partition coefficient generally refers to the concentration ratio of un-
ionized species of compound, whereas the distribution coefficient refers to the
concentration ratio of all species of the compound (ionized plus un-ionized).
 In Pharmaceutical/Chemical Sciences, both phases are usually solvents. Most
commonly polar solvent- water and non-polar solvent- octanol.
 Partition coefficients are useful in estimating the distribution of drugs within the body.
Hydrophobic drugs with high octanol-water partition coefficients are mainly
distributedto hydrophobic areas such as lipid bilayers of cells. Conversely,
hydrophilic drugs (low octanol/water partition coefficients) are found primarily in
aqueous regions suchas blood serum
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  A more polar, hydrophilic compound will have a lower log P (the value can even be
negative), and prefer to “reside” in the aqueous phase. (Log P < 0)
 More non-polar, hydrophobic compounds will have a higher log P, and will partition
into an organic phase. Typical values range from -3 (polar) to 7 (non-polar). (Log > 0)
 Log P also depends on substituents hydrophobic (hydrophobicity constant; π>0) or
hydrophilic (π<0).
π = Log P (substituted compound) – Log P (Parent compound)
π = Log (RX/RH)
Hydrophobic (π>0) Hydrpophili
CH3 0.56 NO2 -0.28
C(CH3)3 1.98 OH -0.67
C6H5 1.96 COOH -0.32
C6H11 2.51 NH2 -1.23
CF3 0.88 CHO -0.65

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 Component log PO/W T (°C)
Acetamide −1.16 25
Methanol −0.81 19
Formic acid −0.41 25
Diethyl ether 0.83 20
p-Dichlorobenzene 3.37 25
Hexamethylbenzene 4.61 25

 In QSAR, we can calculate the log P value by following equation

Log P(compound) = Log P (ring) + π (group 1) + π (group 2)..
 Hansch’s Substitution Constant/
Hydrophobicity Constant; π
Example :
Q. find out the Log P of m-chlorobenzamide;
Log P (benzene)= 2.13,
π(cl) = 0.71,
π(CONH2) = -1.49

ANS
Log P(m-chlorobenzamide) = Log P (benzene) + π (Cl) + π (CONH2)
= 2.13 + 0.71 – 1.49
= 1.35

Q. find out the Log P of p-cresol

Log P (benzene)= 2.13,
π(OH) = -0.67,
π(CH3) = 0.52

Log P(m-cresol) = 2.13-0.67+0.52 = 1.98

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 Hammet’s Electronic Parameter
 The Hammett Plot is a type of Linear Free-Energy Relationship (LFER) analysis
designed to model the electronic effect of substituents on aromatic systems (in the
para and meta positions only).
 This equation was developed and published by Louis Plack Hammett in 1937
 Information gathered can be used to probe the mechanism of the reaction and
can beapplied in the optimization of reaction conditions.
 Hammett equation accounts for how field, inductive, and resonance effects influence
reaction rates
Relationship of o to new reactions
Consider similar reaction

Equation:
Log (Kx/KH) = ρ σ
 Relating the equilibrium constant, Kx, for a given equilibrium reaction with substituent
X and the reference KH constant when X is a hydrogen atom to the substituent
constant σ
 ρ is a correction factor to compare a new reaction to the original

 The reaction constant, or sensitivity constant, ρ, describes the susceptibility of the

reactionto substituents, compared to the ionization of benzoic acid. It is equivalent
to the slope ofthe Hammett plot.

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  ρ>1, the reaction is more sensitive to substituents than benzoic acid and negative charge
is built during the reaction (or positive charge is lost).
 0<ρ<1, the reaction is less sensitive to substituents than benzoic acid and negative
charge is built (or positive charge is lost).
 ρ=0, no sensitivity to substituents, and no charge is built or lost.
 ρ<0, the reaction builds positive charge (or loses negative charge).

Dissociation Constant (Ka) of substituted benzoic acid (K x 105, at 25 C)

Ka of Substituents

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 Taft’s Steric Parameter (Es)
 The Taft equation is a linear free energy relationship (LFER) used in physical
organic chemistry in the study of reaction mechanisms and in the development of
quantitative structure–activity relationships for organic compounds. It was
developed by Robert W. Taft in 1952 as a modification to the Hammett equation
 While the Hammett equation accounts for how field, inductive, and resonance
effects influence reaction rates, the Taft equation also describes the steric effects
of a substituent. The Taft equation is written as:

RCOOCH3 + H2O RCOOH + CH3OH

Es = Log (KRCOOCH3/KCH3COOCH3)
Log (KS/KCH3) = ρ* σ* + δ Es
 Log (KS/KCH3) is ratio of the rate of the substituted reaction
compared to the reference reaction,
 ρ* is the sensitivity factor for the reaction to polar effects,
 σ* is the polar substituent constant that describes the field
and inductive effects of the substituent,
 δ is the sensitivity factor for the reaction to steric effects,
 Es is the steric substituent constant .

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  the polar sensitivity factor ρ* for Taft plots will describe the susceptibility of a
reaction series to polar effects. When the steric effects of substituents do not
significantly influence the reaction rate the Taft equation simplifies to a form of the
Hammett equation

Log (KS/KCH3) = ρ* σ*

 If ρ* > 1, the reaction accumulates negative charge in the transition state and is
accelerated by electron withdrawing groups.
 If 1 > ρ* > 0, negative charge is built up and the reaction is mildly sensitive to polar
effects.
 If ρ* = 0, the reaction is not influenced by polar effects.
 If 0 > ρ* > −1, positive charge is built up and the reaction is mildly sensitive to polar
effects.
 If −1 > ρ*, the reaction accumulates positive charge and is accelerated by electron
donating groups.
 Similar to the polar sensitivity factor, the steric sensitivity factor δ for a new reaction
series will describe to what magnitude the reaction rate is influenced by steric effects.
When a reaction series is not significantly influenced by polar effects, the Taft
equation reduces to:
Log (KS/KCH3) = δ Es
 A plot of the ratio of the rates versus the Es value for the substituent will give a straight
line with a slope equal to δ.

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  If δ is positive, increasing steric bulk decreases the reaction rate and steric effects are
greater in the transition state.
 If δ is negative, increasing steric bulk increases the reaction rate and steric effects are
lessened in the transition state

Constants used in the Taft equation

Substituent Es σ*
–H 1.24 0.49
–CH3 0 0
–CH2CH3 –0.07 –0.1
–CH(CH3)2 –0.47 –0.19
–C(CH3)3 –1.54 –0.3
–CH2Ph –0.38 0.22
–Ph –2.55 0.6

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 Hansch Analysis
 QSAR based on Hammett’s relationship utilize electronic properties as the
descriptors of structures. Difficulties were encountered when investigators attempted
to apply Hammett-type relationships to biological systems, indicating that other
structural descriptors were necessary.
 In 1962, Hansch et al entered the scenario with the numerical information on
lipophilicity, electronic, and steric effect on the model development. The general
form of Hansch equation is as follows:

Log BA = a log p + b σ + c Es + constant (linear)

Log BA = a log p + b (log p)2 + c σ + d Es + constant (nonlinear)
 Partition coefficient; log P
 Hammett constant; σ
 Taft’s steric parameter; Es

 Hansch model correlates biological activity with physicochemical properties. The

coefficients (a, b, c, d, and constant) are determined by multiple regression analysis.

Free-Wilson Analysis
 It is also known as the additivity model or de novo approach. This method is based on the
assumption that the introduction of a particular substituent at a particular molecular
position always contributes in the same way to the biological potency of the whole
molecule, as expressed by the equation:
Log BA = contribution of unsubstituted parent compound + contribution of corresponding
substituents
Log BA = μ + Σ ai aj
 where ai = number of positions at which
substitution occurs
 aj = number of substituents at that position
 μ = overall average.
 The equation is solved by MLR using the presence (1) or absence (0) of the different
substituents as independent parameters, while the measured activity serves as
dependent variable.

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 PHARMACOPHORE MODELLING
 The pharmacophore concept was introduced by Paul Ehrlich in the early 1900s. Then,
the term pharmacophore was coined by Schueler in his 1960 book Chemobiodynamics
and Drug Design, and was defined as “a molecular framework that carries (phoros) the
essential features responsible for a drug’s (pharmacon) biological activity.”
 In those year’s pharmacophore was understood as chemical or functional groups on a
molecule that are responsible for the biological activity.
 In 1997, IUPAC (International Union of Pure and Applied Chemistry) defined
pharmacophore as the sum of steric and electronic properties that are required for the
interaction of a molecule with a target and thus provide the biological activity
 A pharmacophore does not represent a real molecule or a set of chemical groups, but
is an abstract concept; “A pharmacophore is the pattern of features of a molecule that
is responsible for a biological effect,” which captures the essential notion that a
pharmacophore is built from features rather than defined chemical groups.

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  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 donors (HBD), hydrogen bond
acceptors (HBA), positive features, negative features, aromatic rings, hydrophobic
features and their combinations.
 A pharmacophore model includes several patterns arranged in a particular 3D (three
dimensional) pattern. Each pattern is depicted by a typical sphere containing radius
that determines the deviation tolerance from the exact position. There are also
various other displaying ways. These patterns can be displayed as a single pattern or
their combination

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Approaches of Pharmacophore Modeling
 There are two principal approaches of pharmacophore modeling that are used in the drug
discovery process: Ligand-based pharmacophore modeling and structure-based
pharmacophore modeling.
 In the ligand-based pharmacophore modeling approach, novel ligands are designed by
using a set of active ligands available. This approach is employed if the target structure isnot available.
In a similar manner, the structure-based pharmacophore approach is employed when the structure of
the target protein is available.

Ligand Based Drug Design

 In the ligand-based pharmacophore modeling, first active ligands are identified by using
the literature available or database search. The data set is split into a training set and test
set.
 Then, feature analysis of the training set ligands is done. The common features are
detectedthrough the alignment of the active ligands.
 The next step is pharmacophore model generation and ranking of the generated
models. Finally, pharmacophore model validation is performed and the best
pharmacophore modelis selected depending on the results obtained.
Structural Based Pharmacophore Modeling
 In the structure-based pharmacophore modeling, selection and preparation of target
protein structure is the first step.

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  The second step is binding site prediction. Then, complemental chemical features of the
binding site amino acids and their layouts are identified by analyzing it carefully.
 After this, the pharmacophore features, which should be optimized by the adjusted
tools in the programs employed, are generated.
 Finally, crucial pharmacophore features responsible for the activity are selected.
 LigandScout , MOE, Pocket v2 and Snooker are among the commonly used
software for structure-based pharmacophore modeling. Similarly, there are various
software and servers used in pharmacophore modeling.
 The commonly employed programs and servers are summarized in the alphabetical
order(Table 1).

Table 1: Programs and servers used in pharmacophore modeling. Program/Server Brief Description
CATALYST-HipHop CATALYST is now part of the BIOVIA Discovery Studio. It consists
of algorithms used in pharmacophore generation: HipHop and
HypoGen. HipHop gives the alignment of active ligands against a
specific target and finds the three dimensional arrangements of
common features by overlapping various structures.
CATALYST-HypoGen It generates hypotheses that are able to estimate the activity of
molecules quantitatively by using biological analysis data. Thus, it
allows the correlation of the structural and activity data for
pharmacophore modeling.
GALAHAD The program uses modified genetic algorithm and fixes certain
shortcomings of the GASP program and thus increases its
performance. It increases the computational speed by using prebuilt
structures as a starting point.
GASP GASP is available in the SYBYL package. It uses genetic algorithm
for the detection of pharmacophores. Unlike the other pharmacophore
determinations, conformational search is carried out instantly in the
GASP process and is an integral part of the program. A single low
energy structure and random spinings are applied to examine
conformational changes before superimposing on each input
compound.
LigandScout Though it is possible to perform both structure-based and ligandbased
phamacophore modeling with LigandScout, it is among the first
programs specialized in structure-based pharmacophore modeling.

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 Especially, if the structure of the target protein is present in its ligand
bound state, LigandScout is widely used.
MOE MOE is able to perform ligand-based and structure-based
pharmacophore modeling. Model building is performed by the
pairwise alignment of the active ligands. It is recommended to
decrease the magnitude of the training set by grouping similar
molecules.
PharmaGist It is a freely accessible server used in ligand-based pharmacophore
generation. This web server detects pharmacophores via multiple
flexible alignments of the input molecules.
Pharmer It is a pharmacophore method that makes searching based on the width
and complexity of the query instead of the molecular library screened.
It is a very fast method and its source code is available under an open-
source license.
PharmMapper It is a freely accessible web server used for the identification of
potential targets for the input ligands. It calculates pharmacophores by
using semi-rigid pharmacophore mapping.
PHASE It is provided by Schrödinger package. It is a convenient approach
used in drug discovery with or without its receptor structure. It creates
a hypothesis from one or more ligands, protein-ligand complexes and
apo proteins. It has a special algorithm designed for use in
optimization of lead compounds and virtual screening.

Application
 Pharmacophore modeling is employed in virtual screening, fishing drug targets,
ligand profiling, docking, and ADMET prediction.
 New perspectives are also expected for various applications of pharmacophore
modeling in the future due to the simplicity and versatility of the concept. In this
way, besides the applications explained here, it may have applications in
polypharmacology, drug repurposing and side effect prediction

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Source:
1. Yang et al., 2010, Drug Discovery Today, 15(11), 444-450. Doi:
https://doi.org/10.1016/j.drudis.2010.03.0134
2. Muhammed and Akı-Yalçın, JOTCSA. 2021; 8(3): 749-762. https://doi.org/ 10.18596/jotcsa.927426.

3. Qing et al. Journal of Receptor, Ligand and Channel Research. 2014;7:81-92

https://doi.org/10.2147/JRLCR.S46843

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.

 Signal transduction is dependent on the interactions of physiologically significant

substances such as proteins, nucleic acids, carbohydrates, and lipids

 The goal of docking studies is to optimize the shape of both the ligand and protein, as well
as the relative orientation of the protein and ligand, to reduce the total system’s free energy

Target
Protein

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Types of Docking

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

Theories

Lock & Key Theory:

Emil Fischer created a concept termed the "lock-andkey model” in 1890, as seen in figure, to
describe how biological processes operate

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 Fig. : The lock and key theory

The induced-fit theory

Daniel Koshland proposed the "induced fit theory" in 1958. The fundamental concept is that
throughout the character recognition, both the ligand and target, as seen in figure, adapt to one
another by modest conformational changes until an ideal match is reached.

Fig. 5: Induced fit model

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Molecular Docking Approaches

Monte carlo approach

It creates a randomized conformation, translations, and rotation of a ligand in an active site. It
assigns an initial configuration value. Then it develops and scores a new configuration. It
determines if the new configuration is kept using the Metropolis criterion. (Metropolis
criterion- If a new approach outperforms the prior one, it is approved instantly.

Matching approach
This strategy emphasizes idleness, the optimal location of the ligand atom in the site is
determined, resulting in a ligand-receptor arrangement that might also need improvement.

Ligand fit approach

Ligand fit is a word that refers to a quick and precise methodology for docking small molecules
ligands into protein active sites while taking shape complementarity into account

Point complimentarily approach

These techniques are focused on comparing the shapes and/or chemical properties of different
molecules. Blind Docking: This technique was developed to identify potential peptide ligand
binding sites and mechanisms of action by scanning the full interface of target molecules

Software
There is several other software are available for docking such as Discovery studio, ArgusLab,
Schrödinger, Hammerhead, ICM, MCDock, GOLD, GemDock, Glide, Flex-X, Autodock and
Yucca
Application
 Drug Design
 Hit identification
 Lead optimization
 Ligand Preparation
 Selection of target site
 Receptor preparation

Source: Raval K, Ganatra T. Basics, types and applications of molecular docking: A review. IP Int J Comprehensive Adv Pharmacol
2022;7(1):12-16. DOI: https://doi.org/10.18231/j.ijcaap.2022.003

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