1

Drug discovery and Drug discovery and

University of Tripoli
Faculty of pharmacy
Drug discovery and Drug discovery and
development development
3
rd
year pharmacy y p y
S. M. Bensaber
Tripoli
2013 / 2014
1
DEVELOPMENT OF DRUGS ( DRUG DESIGN ) 12hrs
A- Sources of Drugs.
1- Natural sources
2- Semisynthetic drugs
3- Synthetic drugs.
B- Genesis of Drugs.
1- Serendipity ( Accidental discovery )
2- RandomScreening 2 Random Screening .
i- Rationally directed random screening .
ii- Rationally directed metabolite approach .
3- Extraction from natural sources.
4- Molecular modifications
i- General processes. ii- Special processes.
- Simplification ( Disjunction).
-Replication.
- Hybridization.
-Addition.
-Vinylogy principle
- Increase or decrease of the alkyl chain .
- Isosteric substitution ( isosteres and bioisosters).
- Introduction of a bulky group .
Electronwithdrawing andelectrondonatinggroups
C- Soft and hard drugs .
D- Drug latentiation .
- Prodrugs - Bioprecursors - Targeted drugs
E- Anti metabolite approach .
- Electron withdrawing and electron donating groups.
- Others .
iii- Methods of lead optimization.
- Topless sequential method ( pi , sigma , Es)
2
2
Drug Discovery & Development:
Human clinical trials
(2-10 years)
The discovery phase
The Clinical phase
3
FDA approval
(2-3 years)
Identify disease
Target identification
The discovery phase
Drug Discovery & Development:
The drug discovery is a lengthy,
expensive, and complicated process,
Target identification
and validation
Lead discovery &
optimisation
Processing
chemistry
that requires the collaboration of a
large number of research scientists
with skills ranging from computational
and structural chemistry, through
synthetic organic chemistry, molecular
Pre-clinical testing
In vitro
Pre-clinical testing
In vivo
cell biology, genomics, proteomics,
physiology, pharmacology, toxicology,
and clinical biochemistry, amongst
others.
4
3
Identify disease
Selection of a disease target:
Acceptable therapies are available today for many conditions, y y
e.g. (Antibiotics for bacterial diseases etc, paracetamol /
ibuprofen etc. for moderate pain relief).
New agents must have statistically proven clear advantages
over existing therapy (not just that it is clinically effective).
5
Target identification
and validation
A bio(macro)molecule may be involved in a disease
process, but to be a drug target it has to be validated. g g
In other words shown to be critical in the disease process.
Useful techniques available are to validate a target such as
Gene knockout and RNA interference.
6
4
A lead compound is a compound from a series of related
compounds that has some of a desired biological activity
Lead discovery &
optimisation
compounds that has some of a desired biological activity.
This molecule can be characterised, and modified to
produce another molecule with a better profile of wanted
properties to unwanted side effects.
A lead compound is a first foothold on the drug discovery p g y
ladder.
It takes much more effort to make a lead compound into a
drug candidate
7
TESTING DRUGS
Biological tests are required in order to find lead
compounds and for drug optimisation
Tests can be in vivo or in vitro
A combination of tests is often used in research
programmes
Pre-clinical testing
In vitro
Pre-clinical testing
In vivo
8
5
Tests not carried out on animals/humans
Tests carried out on target molecules (enzymes or receptors)
Cells (e.g. cloned cells)
Pre-clinical testing
In vitro
Cells (e.g. cloned cells)
Tissues (e.g. muscle tissue)
Organs
Micro-organisms (for antibacterial agents)
More suitable for routine testing
Measure the interaction of a drug with the target but not the
ability of the drug to reach the target
Does not demonstrate a physiological or clinical effect(s)
Does not identify possible side effects and effective prodrugs
9
Identify competitive or non competitive inhibition
Enzyme Inhibition Tests
Pre-clinical testing
In vitro Examples
Strength of inhibition measured as IC
50
IC
50
=concentration of inhibitor required to reduce enzyme
activity by 50%
10
6
Not easy to isolate membrane bound receptors Not easy to isolate membrane bound receptors
Testing with Receptors
Pre-clinical testing
In vitro Examples
Carried out on whole cells, tissue cultures, or isolated organs Carried out on whole cells, tissue cultures, or isolated organs
Affinity Affinity -- strength with which compounds bind to a receptor strength with which compounds bind to a receptor
Efficacy Efficacy -- measure of maximum biochemical effect resulting measure of maximum biochemical effect resulting
from binding of a compound to a receptor. from binding of a compound to a receptor.
Potency Potency - - concentration of an agonist required to produce concentration of an agonist required to produce 50 50% %
of the maximum possible effect. of the maximum possible effect.
11
Pre-clinical testing
In vivo
Carried out on live animals or humans
Measure an observed physiological effect Measure an observed physiological effect
Measure a drugs ability to interact with its target and its
ability to reach that target
Can identify possible side effects
Transgenic animals - genetically modified animals
Drug potency
Therapeutic ratio/index -
12
7
1- Natural sources, 2- Semisynthetic drugs, 3- Synthetic drugs.
Sources of Drugs.
13
TARGET DISEASE
Priority for the Pharmaceutical Industry
Can the profits from marketing a new drug outweigh the
cost of developing and testing that drug?
Questions to be addressed
Is the disease widespread?
(e.g. cardiovascular disease, ulcers, malaria)
Does the disease affect the first world?
(e.g. cardiovascular disease, ulcers)
Are there drugs already on the market?
If so, what are their advantages and disadvantages (e.g.
side effects)
Can one identify a market advantage for a new therapy?
14
8
DRUG TARGETS
A) Lipids
Cell membrane lipids
B) Proteins )
Receptors
Enzymes
Carrier proteins
Structural proteins (tubulin)
C) Nucleic acids
DNA
RNA
D) Carbohydrates
Cell surface carbohydrates
Antigens and recognition molecules
15
DRUG TARGETS
Between species
Antibacterial antifungal and antiviral agents
Target selectivity
Antibacterial, antifungal and antiviral agents
Identify targets which are unique to the invading
pathogen
Identify targets which are shared but which are
significantly different in structure
Within the bodyy
Selectivity between different enzymes, receptors etc.
Selectivity between receptor types and subtypes
Selectivity between isozymes
Organ and tissue selectivity
16
9
The Lead Compound
A compound demonstrating a property likely to be
therapeutically useful
The level of activity and target selectivity are not crucial
Used as the starting point for drug design and development
Found by design (molecular modelling) or by screening
compounds (natural or synthetic)
N d t id tif it bl t t i d t fi d l d d Need to identify a suitable test in order to find a lead compound
Active Principle - a compound that is isolated from a natural
extract and which is principally responsible for the extracts
pharmacological activity. Oftenused as a lead compound.
17
Sources of Lead Compounds
A) The Natural World
Plantlife (flowers, trees, bushes)
Micro-organisms (bacteria, fungi)
Animal life (frogs, snakes, scorpions)
Biochemicals (Neurotransmitters, hormones)
B) The Synthetic World
( , )
Marine chemistry (bacteria, fish etc)
Chemical synthesis (traditional)
Combinatorial synthesis
C) The Virtual World
Computer aided drug design
18
10
Identification of Lead Compounds
A) Isolation and purification
Solvent-solvent extraction
Chromatography
Crystallisation Crystallisation
Distillation
B) Structure determination
Elemental analysis
Molecular weight
Mass spectrometry p y
Infra red spectroscopy
Ultra violet spectroscopy
MNR (
1
H,
13
C,
2
D) spectroscopy
X-Ray crystallography
19
1- Natural product screening
I- Discovery and structural modification
of lead compounds
A- Discovery of lead compounds
2- Drug discovery via random screening of synthetic
organic compounds
3- Drug discovery via targeted dedicated screening and
rational design
4 Drug discovery via metabolism studies 4- Drug discovery via metabolism studies
5- Drug discovery from the observation of side effects
6- Pharmacophore-based drug design
20
11
PLANT EXTRACTS
OPIUM - Morphine
1- Natural product screening
OPIUM - Morphine
CINCHONA BARK - Quinine
YEW TREE - Taxol
21
PLANT EXTRACTS
WILLOW TREE - SALICYLIC ACID
1- Natural product screening
COCA BUSH - COCAINE
Aspirin
OH
O OH
Acetic
anhydride
O
O OH
CH
3
O
Me
Procaine
N
Me
O
H
H
CO
2
Me
C
O
O
C
O
N
NH
2
CH
3
CH
3
22
12
MICRO-ORGANISMS
N
S CH
3
H H H
N
R
O
O OH O OH O
NH
2
OH
H
2
N C
HN
NH
HN C
NH
NH
2
H
OH
H HO
H
H
OH
H
1- Natural product screening
N
CH
3
O
CO
2
H
S
H
N
H H
C
O
R
Cl
OH
NMe
2
HO Me
H
O
2
N
CH
2
OH
HO
H
O
O
O
O
OH
H
H
CHO
OH
H
Me
CH
2
OH
H
HO
H
OH
H
H
MeHN
H
H PENICILLIN TETRACYCLINES
N OAc
CO
2
H
O
2
HN H
C
O CHCl
2
CEPHALOSPORINS
STREPTOMYCIN
CHLORAMPHENICOL
23
VENOMS AND TOXINS
O O
C
O
N
H
CHC
O
H
N CHC
O
N
C
O
N
C OH
O
Teprotide Teprotide
1- Natural product screening
H
2
N CHC
CH
2
O
CH
2
C
OH
O
N
H
CHC
CH
2
O
HN
N
C
O
N
H
CHC
CH
2
O
CH
2
CH
2
NH
C
NH
2
NH
N
CH
2
CH
2
C
NH
2
O
CHCH
3
CH
2
CH
3
O
C OH
O
Captopril
(anti-hypertensive)
CH
3
C N
HS
24
13
ENDOGENOUS COMPOUNDS NATURAL LIGANDS FOR RECEPTORS NATURAL LIGANDS FOR RECEPTORS
HO
H
N
Me
OH
HO
OH
H
N
Agonist Agonist
1- Natural product screening
HO
ADRENALINE
HO
SALBUTAMOL
gg
O N
H
OH
Antagonist Antagonist
HO
HO
H
N
Me
OH
PROPRANOLOL
O
ADRENALINE
HN
N
Me
S
H
N NHMe
CN
CIMETIDINE
HN
N
NH
2
HISTAMINE
Antagonist Antagonist
25
2- Drug discovery via random screening of synthetic
organic compounds
Random screening - only approach before 1935; screen
every compound you have; still a useful approach;
streptomycin and tetracyclines identified in this way p y y y
High-throughput Screens (HTS)
Very rapid, sensitive in vitro screens
Can assay 100,000 compounds a day
1990 ~200,000 compounds screened per year
1995 5 6 10
6
compounds screened per year 1995 ~5-6 10
6
compounds screened per year
2000 >50 10
6
compounds screened per year
in a large pharmaceutical company
So far, no increase in rate of the number of drugs
coming on the market.
26
14
3- Drug discovery via targeted dedicated screening and
rational design
Nonrandom (or Targeted or Focused) screening - only
screen compounds related to active compounds
Rational approaches - identify causes for disease states:
imbalance of chemicals in the body
invasion of foreign organisms
aberrant cell growth
Identify biological systems involved in disease states;
Structure-Activity Relationships (SARs) & Molecular modelling
Identify biological systems involved in disease states;
use natural receptor ligand or enzyme substrate as the lead;
a known drug also can be used as a lead
27
4- Drug discovery via metabolism studies
Drug metabolism studies - metabolites produced are
screened for the same or other activities
28
15
5- Drug discovery from the observation of side effects
Clinical observations - newactivities found in clinical trials;
29
5- Drug discovery from the observation of side effects
30
16
Determine the effects of structural changes on activity of
drug: structure-activity relationships (SARs)
6- Pharmacophore-based drug design
The Pharmacophore of a drug molecule is that portion of The Pharmacophore of a drug molecule is that portion of
the molecule containing the essential organic functional
groups that directly interact with the target active site and
therefore, confers on the molecule the biological activity of
interest.
31
If you know the pharmacophore for your target, you can
Design new structures.
6- Pharmacophore-based drug design
Design: use analyzed data to design new compounds -
hopefully with better properties
Why make new lead compounds?
Increase activity (make binding stronger)
Decrease side effects (increase selectivity)
Improve ease and efficiency of administration to patient
Potentially find a better synthetic route
y p p y g , y
create newlead compounds based on the pharmacophore!
y y
32
17
Simple example 1: 3D structures are known (active molecule)
1. Data collection: biological activity of lead compound (and
other compounds)
6- Pharmacophore-based drug design
2 Analysis: biologically active molecules share the same 2. Analysis: biologically active molecules share the same
pharmacophoric features (superimpose 3D structures & find
common features)
33
6- Pharmacophore-based drug design
Simple example 1:
3. Design new structures. New molecular mimic will be
tested.
34
18
- Simplification ( Disjunction).
i- General processes.
I- Discovery and structural modification of lead
compounds
B- Molecular modifications of lead compounds
p ( j )
-Replication.
- Hybridization.
-Addition.
-Vinylogy principle
- Increase or decrease of the alkyl chain .
Isosteric substitution( isosteres and bioisosters)
ii- Special processes.
-Isosteric substitution ( isosteres and bioisosters).
- Electron withdrawing and electron donating groups.
- Others .
iii- Methods of lead optimization.
- Topless sequential method ( pi , sigma , Es)
35
1- Simplification ( Disjunction).
i- General processes.
Once a biologically active compound is found, a common first method is
B- Molecular modifications of lead compounds
Example: ergot alkaloids like
to simplify it to determine the essential parts for activity.
For complexmolecules, this often leads to easier synthesis.
Will not be successful if all parts of the molecule are neededfor activity
bromocriptine were starting points
for simplified synthetic analogs
shownbelow
36
19
Synthesis & Evaluation simpler analogs of lead compound Ex. Opioid
analgesic: like morphine & genesis of local anesthetic which prepared
1- Simplification ( Disjunction).
i- General processes.
B- Molecular modifications of lead compounds
analgesic: like morphine & genesis of local anesthetic which prepared
throughsimplification of cocaine
Morphine Cocaine
37
1- Simplification ( Disjunction).
i- General processes.
Molecular modifications
Morphine
38
20
2- Molecular Replication & Hybridization
i- General processes.
-The association of two identical pharmacophoric entities will
B- Molecular modifications of lead compounds
generate an "identical twin drug" which is equivalent to a
homodimer derivative.
-A compound, where two different pharmacological entities are
bounded, is called a "non-identical twin drug" or heterodimer.
The first design strateg is eq i alent to a d plication / -The first design strategy is equivalent to a duplication /
dimerization process of an active compound or lead.
-The aim of this approach is the production of a more potent
and/or more selective drug compared to the single entity.
39
i- General processes.
2- Molecular Replication & Hybridization
B- Molecular modifications of lead compounds
dual acting drugs
symbiotic approach
40
21
4- Molecular addition:
i- General processes.
Weak forces as (electrostatic and hydrogen bonding)
Ex Methenamine Mandelate [ Methenamine +Mandelic acid ]
B- Molecular modifications of lead compounds
Ex. Methenamine Mandelate [ Methenamine +Mandelic acid ]
Methenamine
N
O
+
Methenamine Mandelate
Mandelic acid
N NH
N
O H
O
-
41
ii- Special processes.
B- Molecular modifications of lead compounds
1- Increase or decrease of
the alkyl chain .
42
22
2- Vinylogy principle
ii- Special processes.
-The vinylogy principle was first formulated by Claisen in 1926, who
B- Molecular modifications of lead compounds
The vinylogy principle was first formulated by Claisen in 1926, who
observedfor formylacetone acidic properties similar to that of acetic acid.
-The vinyl group plays the role of an electron-conducting channel
betweenthe carbonyl and the hydroxyl group.
-The same effect explains the acidity of ascorbic acid.
43
2- Vinylogy principle
ii- Special processes.
B- Molecular modifications of lead compounds
44
23
3- Isosteric substitution ( isosteres and bioisosters).
ii- Special processes.
Common alterations of compounds: replacement of groups with
isosteres
B- Molecular modifications of lead compounds
Examples:
OH isosteres: SH, NH
2
, CH
3
O isosteres: S, NH, CH
2
H isostere: F
O N
H
N
H
isosteres.
Isosteres: atoms or groups of atoms which have the same valence
amide
pyrrole
45
Classical and non-classical bioisosteres
for the classical ones, where size equivalence is the key, the
replacement should have roughlythe same size
ii- Special processes.
B- Molecular modifications of lead compounds
replacement should have roughlythe same size.
The key replacements (for example, the C, O, and N replacements are
seenfor three of the classical isosteres: CH3-,- OH,- NH2for univalent;
-CH2-, -O-, and -NH- for divalent;
and -COCH2-R (ketone), -COOR (ester), and- CONHR (amide) for the
carbonyl containingcompounds.
You should also be able to make isosteric replacements for the ring
i l t ( i l ti i i l li h ti i th l equivalents (single aromatic rings; single aliphatic rings, or the general
tricyclic replacement).
For example we could change the ester alcohol oxygen (not the carbonyl
oxygen) with a CH2(ketone), NH (amide), or S (thioester).
46
24
If you change an O to CH
2
- sterics same, but no dipole or lone pair
If h OHT SH t i diff t b t till l i
3- Isosteric substitution ( isosteres and bioisosters).
ii- Special processes.
B- Molecular modifications of lead compounds
If you change an OHTo SH - sterics different, but still a lone pair
O N
H
OH
N
H
OH
S N
H
OH
no activity
Example
H
OH
Propranolol (beta blocker)
N
H
OH
HN N
H
OH
no activity
no activity
active
(but less than
Propranolol)
47
ii- Special processes.
3- Isosteric substitution ( isosteres and bioisosters).
B- Molecular modifications of lead compounds
48
25
Common alterations of compounds: replacement of groups with
ii- Special processes.
3- Isosteric substitution ( isosteres and bioisosters).
B- Molecular modifications of lead compounds
bioisosteres.
Bioisosteres - different chemical groups with the same biological activity.
No restrictionon sterics and electronics, unlike classical isosteres.
O O N O N
H
OH
Propranolol (beta blocker)
potent
O N
H
OH
Pindolol
very potent
N
H
49
ii- Special processes.
3- Isosteric substitution ( isosteres and bioisosters).
B- Molecular modifications of lead compounds
50
26
51
52
27
53
54
28
ii- Special processes.
4- Ring expansion/contractions - changes geometry
B- Molecular modifications of lead compounds
55
5- Ring variations - may add a binding interaction with
heteroatom;
ii- Special processes.
B- Molecular modifications of lead compounds
56
29
6- Extend structure by adding a functional group to lead
compound
ii- Special processes.
B- Molecular modifications of lead compounds
57
7- Extend or contract linking chain length between groups
ii- Special processes.
B- Molecular modifications of lead compounds
58
30
-Limit number of possible conformations
-Canhelp identify bioactive conformation
ii- Special processes.
8- Rigidification
B- Molecular modifications of lead compounds
-Can help identify bioactive conformation
-Locks molecule in most active conformation - more effective
Add a ring
59
Add i id
ii- Special processes.
8- Rigidification
B- Molecular modifications of lead compounds
Add rigid groups
60
31
Add a bulky groups affect conformation; it may affect steric
hindrance
ii- Special processes.
8- Rigidification
B- Molecular modifications of lead compounds
hindrance.
Alter Stereochemistry: usually
different stereoisomers have
different activity different activity
61
H-bond donor or acceptor
Convert to:
II - Binding role of specific functional groups in a molecule
Binding role of hydroxyl groups:
Methyl ether (no H-bond donor now; may cause steric problem)
An ester (no H-bond donor; poor H-bond acceptor; steric problem)
62
32
Methyl ether (no H-bond donor; still H-bond acceptor; may cause steric
problem)
Binding role of hydroxyl groups:
II - Binding role of specific functional groups in a molecule
An ester (no H-bond donor now; poor H-bond acceptor; may cause steric
problem) problem)
63
H-bond donor (if N-H is present) or acceptor; ionic (protonation of N to
forma salt; recall pKa)
Binding role of amino groups:
II - Binding role of specific functional groups in a molecule
forma salt; recall pKa)
Convert to:
Amide (no protonation; no H-bondacceptor now; steric problem).
Tertiaryamine (no H-bonddonor now; still H-bondacceptor; steric).
64
33
Hydrophobic;
Convert to:
Saturated compound (not effective overlap; no pi system; more flexible).
Binding role of aromatic rings, alkenes:
II - Binding role of specific functional groups in a molecule
p ( p p y )
65
H-bond acceptor; dipole-dipole
Convert to:
Alcohol (geometry change can weaken H-bond or dipole-dipole)
Binding role of ketones:
II - Binding role of specific functional groups in a molecule
(g y g p p )
66
34
Hydrophobics/sterics
Convert to:
Longer (homologation) or differently-branched groups
Binding role of alkyl substituents:
II - Binding role of specific functional groups in a molecule
Alkyl groups most easily modified are
DRUG OR DRUG
O
OR
DRUG
O
R
O
DRUG
O
R
H
N DRUG
O
NR
2
DRUG N
CH
3
R
67
Binding role of alkyl substituents:
II - Binding role of specific functional groups in a molecule
Notes:
Recall impact of lipophilicity on drugtransport throughbody
Changing alkyl groups may also affect the preferred conformation of the
molecule!
68
35
Binding role of alkyl substituents:
II - Binding role of specific functional groups in a molecule
69
Example: Nifedipine analogs
CH
3
Binding role of alkyl substituents:
II - Binding role of specific functional groups in a molecule
O
2
N
N CH
3
H
3
C
CO
2
CH
3
H
3
CO
2
C
H
O
2
N
N CH
3
H
3
C
CO
2
CH
3
H
3
CO
2
C
H
O
2
N
N CH
3
H
3
C
CO
2
CH
3
H
3
CO
2
C
H
CH
3
Chemical synthesis of analogs help validate or refute hypotheses
regardingmechanismof action/mode of binding - part of design
Nifedipene
Treats hypertension
Inactive
steric "bump"
Inactive
Different conformation
70
36
various/ sterics
Convert to:
Same substituents at different locations
Different substituents: Recall substituent effects in organic chem!
Binding role of aryl substituents:
II - Binding role of specific functional groups in a molecule
Different substituents: Recall substituent effects in organic chem!
Substituents may affect each others properties (pKa)
71
O MeSO
2
NH
Binding role of aryl substituents:
II - Binding role of specific functional groups in a molecule
O
NR
O MeSO
2
NH
6
8
7
Anti arhythmic benzopyran Anti-arhythmic benzopyran
Best when substituent was at position 7
72
37
H-bondacceptor; dipole-dipole
Convert to:
Hydrolysis products (but will lose a piece); reduce (no more H-bond
Binding role of amides:
II - Binding role of specific functional groups in a molecule
acceptor
73
II - Prodrug
The termprodrug, which was used initially by
Albert HI, is a pharmacologically inactive
compound that is converted into an active drug
byametabolicbiotransformation.
74
38
Prodrug can be classified to two classes:
(1) Carrier linked prodrug
- Temporary linkage of the active molecule with transport moiety
- Mostly of lipophilic nature
Simple hydrolytic reactionled to cleavage of transport moiety - Simple hydrolytic reaction led to cleavage of transport moiety
- Non toxic
- Ability to ensure the release of active principle
(2) Bioprecursors
- Do not imply a temporary linkage between the active principle & carrier
group group
- Result from molecular modification of active principle
- This modification generate new compounds able to be a substrate for the
metabolizing enzymes.
- Metabolite being the expected active principle
- Ability to ensure the release of active principle
75
Prodrug
76
39
Prodrugs for improved lipophilicity or permeability
Prodrugs for improved aqueous solubility
Prodrug: Why
Prodrugs for improved aqueous solubility
Prodrugs for improved parenteral administration
Prodrugs to exploit carrier-mediated absorption
Prodrugs for improved ophthalmic and dermal delivery Prodrugs for improved ophthalmic and dermal delivery
Prodrugs for other purposes
77
Prodrugs for improved lipophilicity or permeability
78
40
Prodrugs for improved aqueous solubility
79
Prodrugs for improved parenteral administration
80
41
Prodrugs to exploit carrier-mediated absorption
81
Prodrugs for improved ophthalmic and dermal delivery
82
42
Prodrugs for other purposes
83
Soft Drugs- These are the opposite of prodrugs. These
compounds are designed and synthesized as ACTIVE ACTIVE
compounds that readily undergo metabolic inactivation to
IV - Soft & Hard Drugs
nontoxic products
Hard Drugs - compounds that contain structural
characteristics required for activity but are not susceptible
to metabolism
Increased efficiency by avoiding metabolism
N t i t b lit f d No toxic metabolites are formed
HOWEVER, less readily eliminated due to lack of
metabolism
84
43
A- Soft Drug
Soft drugs are biologically active drugs
designed to have a predictable and controllable
metabolism to nontoxic and inactive products
after they have achieved their desired
pharmacological effect.
The molecule could be deactivated and
detoxified shortly after it has exerted its
biological effect, thetherapeutic index could be
increased, providingasafer drug.
85
Advantages of Soft Drug
Elimination of toxic metabolites, thereby increasing the
therapeuticindexof thedrug;
Avoidance of pharmacologically active metabolites that
canleadtolong-termeffects;
Elimination of drug interactions resulting from
metaboliteinhibitionof enzymes;
Si lifi i f h ki i bl d b Simplification of pharmacokinetic problems caused by
multipleactivespecies.
86
44
The difference between prodrugs
and soft durgs
The concepts of prodrugs and soft drugs are opposite, as
follow:
A prodrugs is an inactive compound that requires a
metabolic conversion to the active form;
A soft drug is pharmacologically active and uses metabolism
as a means of promoting excretion.
However, it is possible to design a pro-soft drug, a modified
soft drug that requires metabolic activation for conversion to
the active soft drug.
87
B- Hard Drugs
Hard drugs are nonmetabolizable compounds,
characterized either by high lipid solubility and
l ti i di ti d ll accumulation in adipose tissues and organelles or
highwater solubility.
They are poor substrates for the metabolizing
enzymes; the potentially metabolically sensitive
partsof thesedrugsareeither sterically hinderedor
the hydrogen atoms are substituted with halogens
toblockoxidation.
88
45
V - QSAR
Quantitative structure-activity relationships
(QSAR) represent an attempt to correlate
structural or property descriptors of compounds
withactivities.
Thesephysicochemical descriptors, whichinclude
parameters to account for hydrophobicity, p y p y,
electronic properties, and steric effects, are
determined empirically or, more recently, by
computational methods.
89
Activities used in QSAR include chemical
measurementsandbiological assays.
QSAR currently are being applied in many QSAR currently are being applied in many
disciplines, with many pertaining to drug design
andenvironmental riskassessment.
90
46
VI - Molecular Modeling
A technique for the investigation of molecular structures and
properties using computational chemistry and graphical
visualization techniques in order to provide a plausible
three-dimensional representation under a given set of
circumstances.
Computer simulation of molecular structure, to predict and
di l h l l t i i f ti display shape, calculate minimum energy conformations
and dynamic ranges, predict recognition sites, binding
orientations, etc.
91
In Silico Design and Virtual Screening Techniques
Several computational chemistry approaches are based on the
availabilities of the target proteinstructures and known active ligands.
DOCK Receptor-Based Approach
When receptor and ligand structures are both known, the docking
receptor-basedapproachis the most ideal situation.
The ligand can be docked into the known receptor site and molecular
mechanics usedto simulate receptorligandinteractions and dynamics.
Combinatorial-Based Approach
Wh t d li d t t b th k i t l When receptor and ligand structures are both unknown, virtual
combinatorial chemistryapproaches are used.
In this case, computational chemistry is used both to generate
structures and in parallel to perform chemical similarity and diversity
search analysis before and after combinatorial chemistry-based
experimental HTS.
92
47
Ligand-Based Approach
When the receptor structure is unknown but the ligand structures are
known, a ligand-based approach is used. This situation represents the
most commoncase.
De Novo Design-Based Approach
When receptor structure is known and ligand structures are
unknown, de novo design-techniques are used.
In this situation, there is available information about the target , g
receptor, or a similar receptor, but no existing leads that can interact
with the active receptor sites.
93