B. PHARM 6TH SEMESTER DRUG DESIGN. FACTORS, QSAR, DRUG DISCOVERY, DRUG DEVELOPMENT, VARIOUS APPROACHES FOR DRUG DESIGN, PARTITION COEFFICIENT, HAMMETS EQUATION, TAFTS STERIC PARAMETER, HANSCH ANALYSIS

1. PRESENTED BY-
SIDDHI SHRIGIRIWAR
NAGPUR, MAHARASHTRA, INDIA
E-mail- sshrigiriwar9@gmail.com
NAGPUR COLLEGE OF PHARMACY
MEDICINAL CHEMISTRY-III
DRUG DESIGN

2. CONTENTS
➢ DRUG
➢ DRUGDESIGN
➢ FACTORSGOVERNING DRUG DESIGN
➢ DRUGDISCOVERY
➢ DRUGDEVELOPMENT
➢ TYPES OF DRUG DESIGN
➢ LIGAND- BASED & STRUCTURE-BASEDDRUG DESIGN
➢ VARIOUS APPROACHES IN DRUGDESIGN
➢ BASIC CONCEPTS OF DRUG DESIGN
➢ QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP
DRUG DESIGN

3. DRUG
DRUG
Drogue
French word
Means
DRY HERB
PLANT SOURCE
DRUG:
➢ A drug is a substance or a molecule that is used for the prevention diagnosis, cure, mitigation, and
treatment or alleviation of its symptoms. of certain diseases OR abnormal conditions in man and
animals. These are that substances that change or modify a person’s mental or physical condition.
➢ It gives a therapeutic effect to the patient by inhibiting or inducing the function of a biomolecule.

4. DRUG DESIGN
DRUGDESIGN:
The drug is planned or arranged in such a way i.e. inventive process of
searching for new medications based on the knowledge of a biological
target.
Drug design is an important part of discovery. It is a systematic approach to
finding or research, selection, and optimization(most effective) of drug
molecules based on molecular interactions between drug or target
protein or its physicochemical properties.
In the past few decades, the research and discovery of novel medicinal compounds has stopped. This
trendin drug developmenthas increased due to two vital factors;
➢ first is the strict empirical and rational approachto drug designand
➢ second is the high standards of safety and therapeutic efficacy along with the increased cost of
research, development,and clinical trials.

5. DRUG DESIGN
Drug design explains the following:
1) Effects of biological compounds based on molecular interaction in terms of molecular structures
or physicochemical properties of the involvedmolecules.
2) Various processes by which the drugs exert their pharmacological effects.
3) Manner in which the drugs specifically react with the protoplasm to
produce a pharmacological response.
4) Manner in which the drugs are modified, detoxicated, metabolized, or eliminatedby the organism.

6. 1. Smaller the expenditure of human and material resources involved in the production of a new drug of a
particular value, the more viablethe programdesign.
need to be established
2. Experimental animal and clinical screeningoperations of the new drugs.
3. Relationships between chemical features and biological properties
retrospectively
4. QSAR varies based on the natureof the evaluation of structureor activity.
5. The trend to synthesize a large number of novel medicinal compounds for exploratory evaluation still
succeeds, thus reflecting the creative authenticity and functions of an individualized expression of
noveltyby a medicinal chemist.
6. Substituting the moleculewith functional groups that do not necessarily resemblethe metabolites
7. Disease etiologies and various biochemical processes involvedprove useful
FACTORS GOVERNING DRUG DESIGN

7. Stage 2
Stage 1
Stage 4
DRUG DISCOVERY
Stage 3
Drug
Discovery
2-5 years
Preclinical
Developments
1-2 years
Clinical
Development
5-7 years
Regulatory
Approval
1-2 years
100 Projects Millions 1molecule

8. DRUG DEVELOPMENT
Number of compounds
5,000- 50,000
250
5
1
Basic Research
Drug Discovery
Preclinical Research
Clinical Research
Approved Drug
Drug development is the
process of bringing a new
pharmaceutical drug to the
market
compound
identified through
once a lead
has been
the
process of drug discovery.
The entire process of
bringing a new drug to
market. It is an integrated,
multidisciplinary endeavor
that includes drug discovery,
chemistry
pharmacology,
safety
and
non-clinical
testing,
manufacturing, clinical trials,
and regulatory submissions.
5 STAGES FOR DRUG
DEVELOPMENT:
Post Marketing Monitoring

9. TYPES OF DRUG DESIGN
DRUG DESIGN TECHNIQUES
LIGAND- BASED DRUG DESIGN RECEPTOR- BASED DRUG DESIGN
Pharmacophore
Model
QSAR
Molecular
Docking
De Novo Design
VIRTUAL SCREENING
Identification of that molecule that binds to the targeted site or receptor

10. Ligand-BasedDrug Design:
LBDD refers to drug discovery efforts in the absence of any target structures and in the
presence of chemical structures known to modulate the target. The most popular
approaches for ligand-based drug design are the QSAR method and pharmacophore
modeling. QSAR is a computational method to quantify the correlation between the
chemical structures of a series of compounds and a particular chemical or biological
process. Alsoknowndirectas directdrugdesign.
Structure-BasedDrug Design:
SBDD is an iterative process and it proceeds through multiple cycles leading an
optimized drug candidate to clinical trials. Generally, a drug discovery process consists of four
steps: the discovery phase, the development phase, the clinical trial phase, and the registry
phase. (SBDD) uses computational chemistry tools in which the structure of a protein is
used as the basis to identify or design new chemical compounds that could bind to the
target resulting in the inhibition of the target protein. SBDD uses the 3D shape and
structure of the protein as the basis for designing new drugs. Structures determined by
NMR spectroscopy, X-ray crystallography, and homology modeling. Also known as reverse
Pharmacology.
LIGAND- BASED & STRUCTURE BASED DRUG DESIGN
LBDD
SBDD

11. 1) Quantum Mechanical Approach: Quantum or wave mechanics involve
some essential principles derived from fundamental assumptions that
effectively describe natural phenomena. Quantum mechanics satisfactorily
explain the properties of protons, neutrons, and electrons. The electronic
features of the molecules elicit chemical alterations and form the base of
drug molecule phenomena. (How atomic particles exist and interact with each
other)
2) Molecular Orbital Approach: This approach is based on the assumption
that electrons in molecules are directly linked to the orbitals engulfing the entire
molecule, and this states the molecularorbitaltheory.
The molecular orbital approach shows dependence on
electronic charge (as proven by studying three volatile inhalation anesthetics)
and on molecular conformation (as studied concerning acetylcholine by parameters
like bond lengths and torsionalangles.
VARIOUS APPROACHES IN DRUG DESIGN

12. 3) Molecular Connectivity Approach: This approach establishes the
presence of structural features like cyclisation, unsaturation, skeletal
branching, and the presence and position of the heteroatom in molecules with
a series of numerical indices. For example, in the SAR study of amphetamine-
type hallucinogenic drugs, an index was found to possess a correlative
factor. The molecular connectivity approach has the limitations of
electronegativity variance between atoms, and the non-distinguishable entity
of cis-trans isomerism.
4) Linear Free-Energy Approach: This approach establishes the link
between proper selections of physicochemical parameters with a specific
biological phenomenon. This correlation, however, does not allow a direct
interpretation about molecular structure but offers a clue towards the
selection of candidate molecules forsynthesis.
VARIOUS APPROACHES IN DRUG DESIGN

13. VARIOUS APPROACHES IN DRUG DESIGN
5) Design of Analogues: Aalouge is usually defined as the modification of a
drug molecule or any bioactive compound to prepare a new molecule
showing chemical and biological similarity with the original model
compound. Analogs are these substances that are already in use. They can
be synthesizedby changing the position of the substitutiongroup.
ForExample- Tetracycline Oxytetracycline
6) Design of Lead compound and Lead Discovery: a chemical compound that
shows promise as a treatment for a disease and may lead to the
development of a new drug during lead discovery, an intensive search
ensues to find a drug-like small molecule or biological therapeutic, typically
termed a development candidate, that will progress into preclinical, and if
successful, into clinical development and ultimately be a marketed
medicine.

14. Basic Conceptsof Drug Design
Successful drug design is a multi-step, multi-disciplinary, and multi-year process. Drug discovery is not a
predictable consequence of fundamental basic science; drug design is not just a simple technology of
generating drugs for humans based on biological advances; if it were, much better drugs would be
availablealready.
Medicinal chemistry is a science that provides a molecular bridge between the basic science of
biology and the clinical science of medicine (analogous to chemistry being the central science between
the traditional disciplines of biology and physics). Drugdesign may broadlybe dividedinto two phases:
➢ Basicconcepts about, and drugs, receptors,and drug-receptorinteractions
➢ Basic concepts about drug-receptorinteractions applied to humans.
BASIC CONCEPTS OF DRUG DESIGN

15. Quantitative structure-activity relationship (QSAR) is a ligand-based drug design
method developed more than 50 years ago by Corwin Hansch & Fujita in the early
1960s. extending the concept of Linear Free Energy Relationships (LFER) to describe
the efficacy of a biologically active molecule. It is a mathematical relationship that
correlates, measurable, and calculable molecular properties to some specific
biological activity. The biological activity of a molecular system and its geometrical
and chemical characteristics (identify and quantify). This approach quantitatively
related the structure of a compound to its activity and the resulting equations were
named Quantitative Structure-Activity Relationships (QSAR) or Quantitative
Structure-Property Relationships (QSPR). This method increases the probability of
finding active compounds among the Eventually synthesized ones, thus keeping
synthetic and screening efforts within reasonable limits in relation to the success rate.
PhysicochemicalParameters Used in QSAR
QSAR studies are conducted in groups of related compounds. However, QSAR studies
on structurally diverse sets of compounds are more common. In both cases, a wide
rangeof parameters shouldbe considered.
QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP

16. Partition Coefficient (K)
In order to reach its site of action a drug has to pass through a few biological
membranes. Therefore, organic medium/aqueous system partition coefficients (P) are
the parameters considered for measuring the ease of movement of the drug through
these membranes. The accuracy of the drug activity correlation with partition
coefficients depends on the solvent system used as a membrane model. For example,
consistent results for drugs absorbed in the GIT can be obtained using n-octanol;
consistent correlations for drugs crossing the blood-brain barrier can be obtained using
less polar solvents (like olive oil); and more consistent values for buccal absorption
(soft tissues in the mouth) can be obtained using more polar solvents (like
chloroform).
PARTITION COEFFICIENT
Conc. of drug in organic phase
Partition Coefficient (K) = Conc. of drug in aqueous phase
Organic solvent
Water

17. HAMMET’S ELECTRONIC
COOH
+
COO - + H
K= 6.27*10-5
HAMMET’S ELECTRONIC
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 paraandmetapositionsonly).
The Hammett equation is one of the most widely applied relations between
the structure and reactivity of organic compounds. This equation relates the
relative reactivities of the series of di- and poly-substituted benzene derivatives.
Measures the electron withdrawing or electron donating in comparison to
benzoic acid and howaffectsits ionization.

18. TAFT’S STERIC PARAMETER
STERICPARAMETER
Steric features mainly affect the drug-receptor interaction and reflect the change in the onset or duration of action.
The bulky group may lower the activity by the improper fitting of drugs into binding sites. The size of the substituent
playsan importantrolewithrespect to otherparameters.
Taft's steric factor (Es): This parameter is a measure of substituent size and is useful for studying intramolecular
steric effects, particularly in reactions where the substituent is near the reaction center. It can be measured
experimentally by measuring the effect, that different substituents have on the rate of chemical reaction carried out in
the parent structure. Since the larger substituent next to the reaction center binder the reaction is more than the
smaller substituent. Therefore, the difference between the reaction rates of the parent reaction and the substituted
reaction leads to the measure of substituent size. Since acid hydrolysis of an ester is almost determined by a steric
factor,
Es maybe definedas:
Es= log (K/K0)A
K= Esterhydrolysisrateconstant for substitutedcompound
K0=Esterhydrolysisrateconstant for methylderivative
A=Acidhydrolysis.

19. HANSCH ANALYSIS
HanschEquation:
The biological activity of most drugs is related to a combination
of physicochemical properties. In such cases, simple equations
involving only one parameter are relevant only if the other
parameters are kept constant. In reality, this is not easy to achieve and
equations which relate, biological activity to more than one parameter
are more common. These equations are known as Hansch equations
and they usually relate biological activity to the most commonly used
physicochemical properties (P and/or, n, and a steric factor). If the
range of hydrophobicity values is limited to a small range then the
equationwillbe linearas follows:
Log = log (1/C)= k1 log P + k2o k3E1 + k4

20. Advantages of QSAR
➢ It provides a quantifying relationship betweenthe structure and activity on their physiochemical property
basis.
➢ It is possibleto predictdesignedcompounds beforethe chemicalsynthesis of novelanalogs.
➢ It helps in understanding the interactions between functional groups of designed molecules and the
activityof the targetenzymeor protein
Disadvantages of QSAR
➢ It may provideincorrect correlations dueto biological data experimentalerror.
➢ If there are fewer training sets of molecules, the data may not reflect the complete property and thus cannot be
usedforpredictingactivecompounds.
➢ In some 3D-QSARstudy,ligand-binding receptoror proteinis not available.
➢ It is not necessarythat the QSARstudygivessuccessfulresultson each application.

21. -SIDDHI SHRIGIRIWAR
THANKYOU