FUNCTIONAL GROUP MODIFICATION : Medicinal ChemistryPRUTHVIRAJ K
Once a lead compound or a pharmacophore structure with the desired pharmacological effect has been identified, organic chemists can introduce modifications in the chemical structure of the lead compound with the goal of improving the pharmacokinetics or pharmacodynamics of a drug candidate. These evolved structures are known as analogs.
3
Introduction of Veterinary pharmacologyQaline Giigii
this course of Introduction of veterinary pharacology was presented by Dr. Osman Abdulahi Farah
Osman Shiine
at Gollis University faculty of Veterinary Medicine
2014
Introduction of Veterinary pharmacology Somaliland Dr.Osman Abdulahi FarahQaline Giigii
This course was prepared by Dr.Osman Abdulahi Farah
Cismaan shiine Lecturer of Gollis University Faculty of Agriculture and Veterinary Medicine 2014
The main content of this course including introduction of Veterinary Pharmacology, division of pharmacology and list of terms of terminology about veterinay pharmacology
FUNCTIONAL GROUP MODIFICATION : Medicinal ChemistryPRUTHVIRAJ K
Once a lead compound or a pharmacophore structure with the desired pharmacological effect has been identified, organic chemists can introduce modifications in the chemical structure of the lead compound with the goal of improving the pharmacokinetics or pharmacodynamics of a drug candidate. These evolved structures are known as analogs.
3
Introduction of Veterinary pharmacologyQaline Giigii
this course of Introduction of veterinary pharacology was presented by Dr. Osman Abdulahi Farah
Osman Shiine
at Gollis University faculty of Veterinary Medicine
2014
Introduction of Veterinary pharmacology Somaliland Dr.Osman Abdulahi FarahQaline Giigii
This course was prepared by Dr.Osman Abdulahi Farah
Cismaan shiine Lecturer of Gollis University Faculty of Agriculture and Veterinary Medicine 2014
The main content of this course including introduction of Veterinary Pharmacology, division of pharmacology and list of terms of terminology about veterinay pharmacology
DRUG DISCOVERY
Drug Discovery without a lead
LEAD DISCOVERY/IDENTIFICATION
LEAD MODIFICATION
CONCEPT OF PRODRUGS AND SOFT DRUGS
DRUG RECEPTOR INTERACTIONS
DRUG DISCOVERY
Drug Discovery without a lead
LEAD DISCOVERY/IDENTIFICATION
LEAD MODIFICATION
CONCEPT OF PRODRUGS AND SOFT DRUGS
DRUG RECEPTOR INTERACTIONS
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Rational Drug design
1. RATIONAL DRUG DESIGN
The identification and characterization of a
biological macromolecule implicated in disease
pathology acts as a starting point for rational drug
design. i.e., rational drug design begins with a
hypothesis that modulation of a specific biological
target may have therapeutic value.
Rational drug design can then be used to design a
drug molecule that restores the balance of the
signalling pathway by inhibiting or stimulating the
biological target as appropriate.
In order for a biomolecule to be selected as a drug
target, two essential pieces of information are
required.
2. 1)-The first is evidence that modulation of the target will be
disease modifying. For example, disease linkage studies
that show an association between mutations in the
biological target and certain disease states.
2)-The second is that the target is "druggable". This
means that it is capable of binding to a small molecule
and that its activity can be modulated by the small
molecule.
Once a suitable target has been identified, the target is
normally;
a)- Cloned i.e., DNA of the cell to be cloned is obtained
from an organism of interest, then treated with enzymes
in the test tube to generate smaller DNA fragments.
3. These fragments are then combined with vector DNA to
generate recombinant DNA molecules.
The recombinant DNA is then introduced into a host
organism E. coli bacteria.
This will expand exponentially and generate a
population of organisms in which recombinant DNA
molecules are replicated along with the host DNA and
are called transgenic or genetically modified
microorganisms (GMO).
Each of these transgenic or genetically modified
microorganisms (GMO) contain copies of the original
recombinant molecule. Thus, both the resulting bacterial
population, and the recombinant DNA molecule, are
commonly referred to as "clones".
4. b)- Produced i.e., Protein production is the biotechnological process
of generating a specific protein. This includes the transcription of
the recombinant DNA to messenger RNA (mRNA), the translation
of mRNA into polypeptide chains, which are ultimately folded into
functional proteins and may be targeted to specific sub-cellular or
extracellular locations.
c)- And purified i.e., Protein purification is a series of processes
intended to isolate one or a few proteins from a complex mixture,
usually cells, tissues or whole organisms.
Protein purification is vital for the characterization of the function,
structure and interactions of the protein of interest.
The purification process may separate the protein and non-
protein parts of the mixture, and finally separate the desired
protein from all other proteins.
Separation steps usually exploit differences in protein size,
physico-chemical properties, binding affinity and biological
activity.
The pure result may be termed as protein isolate.
5. The purified protein is then used to establish a
screening assay i.e., high-throughput screening
(HTS), wherein large libraries of chemicals are
tested for their ability to modify the target.
For example, if the target is a novel GPCR (G-
protein coupled receptors), compounds will be
screened for their ability to inhibit or stimulate that
receptor and if the target is a protein kinase, the
chemicals will be tested for their ability to inhibit that
kinase.
6. Ideally the candidate drug compounds should be "drug-
like", that is they should possess properties that are
predicted to lead to oral bioavailability, adequate
chemical and metabolic stability, and minimal toxic
effects.
Several methods are available to estimate
druglikeliness, lipophilic efficiency and predicting drug
metabolism in the scientific literature.
Due to the large number of drug properties that must be
simultaneously optimized during the design process,
multi-objective optimization techniques are sometimes
employed.
But still drug design is very much reliant on serendipity
and bounded rationality.
7. PRO-DRUG
In 1958, Albert initially introduced the term prodrug and used it
to refer to a pharmacologically inactive compound that is
transformed by the mammalian system into an active
substance by either chemical (e.g., hydrolysis or
decarboxylation) or metabolic means.
This included both compounds that are designed to undergo a
transformation to yield an active substance and those that
were discovered accidently to do so.
The type of prodrug to be produced depends on the scientific
aspect of the drug’s action that requires improvement and the
type of functionality that is present in the active drug.
Generally, prodrug approaches are under-taken to improve
patient acceptability of the agent (i.e., reduce pain associated
with administration), alter absorption, alter distribution, alter
metabolism, or alter elimination.
8. MAJOR GROUPS OF PRO-DRUGS
Pro-drugs can be conveniently grouped into carrier-
linked pro-drugs and bio-precursor pro-drugs.
Carrier-Linked Pro-Drugs are drugs that have
been attached through a metabolically labile linkage
to another molecule, the so-called pro-moiety,
which is not necessary for activity but may impart
some desirable property to the drug, such as
increased lipid or water-solubility or site-directed
delivery.
9. Administration of a drug parenterally may cause
pain at the site of injection, especially if the drug
begins to precipitate out of the solution and damage
the surrounding tissue.
This situation can be remedied by preparing a drug
with increased solubility in the administered solvent.
As chloramphenicol has low water solubility so the
succinate ester was prepared to increase the water
solubility of the agent and facilitate parenteral
administration.
10.
11. The succinate ester itself is inactive as an antibacterial
agent, so it must be converted to chloramphenicol for
this agent to be effective.
This occurs in the plasma to give the active drug and
succinate.
The ester hydrolysis reaction can be catalysed by
esterases present in large amounts in the plasma.
The ability to prepare ester-type pro-drugs depends on
the presence of either a hydroxyl group or a carboxyl
moiety in the drug molecule.
The pro-moiety should be easily and completely
removed after it has served its function and should be
nontoxic, as is indeed the case with succinate.
12. Selection Of Appropriate Pro-moiety depends on
which properties are sought for the agent.
If it is desirable to increase water solubility , then a
promoiety containing an ionizable function or numerous
functional groups is used.
If the goal is to increase lipid solubility or decrease water
solubility, a nonpolar promoiety is appropriate.
Mutual Pro-drugs: A slight variation on the carrier-
linked prodrug approach is seen with mutual prodrugs in
which the carrier also has activity.
e.g., The anti-neoplastic agent estramustine, which is
used in the treatment of prostatic cancer, provides an
example of such an approach. (scheme 5-2)
13.
14. Estramustine is composed of a phosphorylated steroid
(17 α-estradiol) linked to a normustard
[HN(CH2CH2Cl)2] through a carbamate linkage.
The steroid portion of the molecule helps to concentrate
the drug in the prostate, where hydrolysis occurs to give
the normustard and CO2.
The normustard then acts as an alkylating agent and
exerts a cytotoxic effect.
The phosphorylated steroid (17α-estradiol) also has an
antiandrogenic effect on the prostate and, thereby, slows
the growth of the cancer cells.
Since both the phosphorylated steroid (17α-estradiol)
and the normustard possess activity so estramustine is
termed a mutual prodrug.
15. Bioprecursor pro-drugs contain no promoiety but
rather rely on metabolism to introduce the
functionality necessary to create an active species.
For example, the nonsteroidal anti-inflammatory
drug (NSAID) sulindac is inactive as the sulfoxide
and must be reduced metabolically to the active
sulfide (scheme 5-3).
16.
17. Sulindac is administered orally, absorbed in the small
intestine, and subsequently reduced to the active
species.
Administration of the inactive form has the benefit of
reducing the gastrointestinal irritation associated with
the sulfoxide.
This also illustrates one of the problems associated with
this approach, namely, participation of alternate
metabolic paths that may inactivate the compound.
In this case, after absorption of sulindac, irreversible
metabolic oxidation of the sulfoxide to the sulfone can
also occur to give an inactive compound.
18. Seen less frequently, some prodrugs rely on
chemical mechanisms for conversion of pro-drug to
its active form.
For example, hetacillin is a prodrug form of
ampicillin in which the amide nitrogen and α-amino
functionalities have been allowed to react with
acetone to give an imidazolidinone ring system
(scheme 5-4).
19.
20. This decreases the basicity of the α-amino group
and reduces protonation in the small intestine so
that the agent is more lipophilic.
In this manner, the absorption of the drug from the
small intestine is increased after oral dosing, and
chemical hydrolysis after absorption regenerates
ampicillin.
In such an approach, the added moiety, or
promoiety, in this case acetone, must be non-toxic
and easily removed after it has performed its
function.
21. COMBINATORIAL CHEMISTRY
Combinatorial chemistry is a new methodology by
which we can simultaneously synthesize a large
number of possible compounds that could be
formed from a number of building blocks.
22. PRINCIPLE OF COMBINATORIAL CHEMISTRY
The basic principle of the combinatorial chemistry is
to produce a large number of compounds at same
time. The characteristic of combinatorial synthesis
is that different compounds are synthesized
simultaneously under identical reaction conditions
in a systematic manner, so that ideally the products
of all possible combinations of the starting materials
will be obtained at once. The collection of these
finally synthesized compounds is referred to as a “
combinatorial library. ”
24. SYNTHETIC METHODOLOGIES FOR PRODUCTION OF
COMBINATORIAL LIBRARIES
Solid-Phase Synthesis
The compound library have been synthesized on
solid phase such as resin bead, pins, or chips.
Solution-Phase Synthesis
In this method synthesis of compounds takes place
in solution form .
25. REQUIREMENTS FOR SOLID – PHASE
SYNTHESIS
Solid supports
Examples:- Polystyrene resins,
Tenta Gel resins,
Polyacrylamide resins,
Glass and ceramic beads etc.,
Linkers
To support the attachment of a synthetic target, the polymer is
usually modified by equipping it with a linker.
Examples:- Wang resins,
Rink resins,
Dihydropyran derivative resins etc.,
Protecting Groups
Examples:- FMOC (Fluro methoxy carbonyl benzyl ester) TBOC
(Tertiary butyloxy carbonyl) etc.,
26. SOLID-PHASE SYNTHESIS
1. Take Solid support.
2. React the solid support with a group called linker.
3. Mix the Solid support (bead) with a substrate that
we want to use in a chemical reaction. The linker
will bind to it and hold it on the Solid (bead).
27. 4. Here we have 6 reaction vessels containing a 6
different reagents. Put a 1/6 of beads into a mesh
bag and put into the reaction vessels.
28. 5. Substrate reacts with the reagent in which they are
placed and forms products on the solid support.
6. The Solid (beads) are removed from the vessel by
lifting the mesh bag and they are washed to remove
any unreacted reagents.
29. 7. The product are separated from solid support by
the breakdown of linkers.
8. The solid supports can be reused.
9. So that 6 different new compounds are
synthesized, which can be now tested for biological
activity. So in this way, the products are obtained by
the solid phase synthesis.
30. METHODS FOR SOLID PHASE SYNTHESIS
Combinatorial synthesis on solid support is usually
carried out by using one of the following methods;
Parallel synthesis
Mix and Split method.
33. APPLICATIONS OF SOLID PHASE SYNTHESIS
Synthesis of 1,4-benzodiazepines,
Synthesis of Benzopyran derivatives,
Synthesis of luteinizing hormone releasing hormon
analogues etc.
34. SOLUTION – PHASE SYNTHESIS
In this method synthesis of compounds takes place
in solution form without the aid of solid support.
35. FUNCTION OF SCAVENGERS
To separate the product from the reagent used in
the reaction easily.
If the reagent is electrophilic, use a nucleophilic
scavenger!
If the reagent is nucleophilic, use an electrophilic
scavenger!
37. SEPARATION & ANALYSIS OF
“COMBINATORIAL LIBRARIES”
Separation and analysis of combinatorial libraries
places high demands on existing analytical
techniques because
(a) The quantities required to be analyzed are very
small.
(b) The analysis is non destructive and allow
recovery of the possible compounds.
(c) The methods must be suitable for rapid parallel
analysis.
38. ANALYTICAL EQUIPMENTS USED IN
COMBINATORIAL CHEMISTRY
HPLC – it is used to separate the compounds of
Combinatorial libraries.
UV Spectrophotometer
IR Spectrophotometer
Hyphenated technique such as HPLC-MS etc;
39. SCREENING METHODS
Screening is a process by which the biologically
active compound are identified among a mixture of
chemical compounds.
The Screening methods used in combinatorial
chemistry are;
High-throughput screening
Virtual screening
40. HIGH - THROUGHPUT SCREENING
High-throughput screening (HTS) involves the
process of finding a active compound against a
chosen target.
41. VIRTUAL SCREENING
Virtual screening refers to the use of computers to
predict whether a compound will show desired
activity or not, on the basis of its two dimensional or
three dimensional chemical structure.
42. APPLICATIONS
1. Mainly it is applied in the discovery of drugs. e.g.,
Raloxifen
2. To synthesize analogues of existing lead structure
to elucidate the Structure Activity Relationships
(SAR).
3. Preparation of hydrazones and discovery of an
antibiotic compound using traditional synthesis
43. While preparation of hydrazones and discovery of
an antibiotic compound using combinatorial
synthesis
45. CONCLUSION
Combinatorial chemistry had revolutionized drug
research by enabling a dramatic reduction in
development time (four to seven years) by
speeding and identification of lead compounds.
Combinatorial chemistry can reduce the time
required for drug discovery from its current average
of 4 years to 1 year.
46. COMPUTER-AIDED DRUG DESIGN
Drug design frequently but not necessarily relies on
computer modeling techniques. This type of modeling is
often referred to as computer-aided drug design.
Ideally, the computational method will be able to predict
affinity before a compound is synthesized and hence in
theory only one compound needs to be synthesized,
saving enormous time and cost.
The reality is that present computational methods are
imperfect and provide, at best, only qualitatively
accurate estimates of affinity.
In practice it still takes several iterations of design,
synthesis, and testing before an optimal drug is
discovered.
Computational methods have accelerated discovery by
reducing the number of iterations required and have
often provided novel structures.
47. Drug design with the help of computers may be used at any of
the following stages of drug discovery:
I. Hit identification using virtual screening (structure- or ligand-
based design)
Virtual screening (VS) is a computational technique used in
drug discovery to search libraries of small molecules in order
to identify those structures which are most likely to bind to a
drug target, typically a protein receptor or enzyme.
II. Hit-to-lead optimization of affinity and selectivity (structure-
based design, QSAR, etc.)
Hit to lead also known as lead generation is a stage in early
drug discovery where small molecule hits from a high
throughput screen (HTS) are evaluated and undergo limited
optimization to identify promising lead compounds.
These lead compounds undergo more extensive optimization
in a subsequent step of drug discovery called lead
optimization.
48. III. Lead optimization for other pharmaceutical
properties while maintaining affinity.
Drug development is the process of bringing a new
pharmaceutical drug to the market once a lead
compound has been identified through the process
of drug discovery.
It includes pre-clinical research on microorganisms
and animals, filing for regulatory status, such as via
the United States Food and Drug Administration for
an investigational new drug to initiate clinical trials
on humans, and may include the step of obtaining
regulatory approval with a new drug application to
market the drug.
49. ANTI-SENSE TECHNOLOGY
During the process of transcription, double-stranded
DNA is separated into two strands by polymerases.
These strands are named the sense (coding or [+]
strand) and the antisense (template or [-] strand).
The antisense DNA strand serves as the template for
mRNA synthesis in the cell. The resulting RNA molecule
is called antisense RNA. The code for ribosomal protein
synthesis is normally transmitted through the antisense
strand.
Antisense RNA sequences were first reported to be
naturally occurring molecules in which endogenous
strands formed complementarily to cellular mRNA,
resulting in the repression of gene expression.
50. Rationally designed antisense oligonucleotide interactions
occur when the base pairs of a synthetic, specifically designed
antisense molecule align precisely with a series of bases in a
target mRNA molecule.
Antisense oligonucleotides may inhibit gene expression
transiently by masking the ribosome-binding site on mRNA,
blocking translation and thus preventing protein synthesis, or
permanently by cross-linkage between the oligonucleotide
and the mRNA.
Most importantly, ribonuclease H (RNase H) can recognize
the DNA–RNA duplex (antisense DNA binding to mRNA), or
an RNA–RNA duplex (antisense RNA interacting with mRNA),
disrupting the base pairing interactions and digesting the RNA
portion of the double helix.
Inhibition of gene expression occurs because the digested
mRNA is no longer competent for translation and resulting
protein synthesis.
51. APPLICATIONS OF ANTI-SENSE
TECHNOLOGY
Antisense technology is beginning to be used to
develop drugs that might be able to control disease
by blocking the genetic code, interfering with
damaged or malfunctioning genes.
Among the possible therapeutic antisense agents
under investigation are agents for chronic
myelogenous leukemia, HIV infection and AIDS,
cytomegalovirus retinitis in AIDS patients, and
some inflammatory diseases.