how to design a drug

1. Drug Design
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2018433061
2018433062

2. What is drug?
A drug is any chemical substance that causes a change in an organism's physiology or psychology
when consumed.
What is drug design?
Drug design is the process of creating a new drug by molecularly altering a lead (parent)
compound to maximize desired effects and minimize undesirable effects.
Several multidisciplinary approaches are used in drug Designing:
• Computational tools
• Methodologies for structure guided approach
• Global gene expression data analysis by softwares

3. 3
Molecular modification is chemical
alteration of a known and previously
characterized lead compound for the purpose
of enhancing its usefulness as a drug.
MOLECULAR MODIFICATION

4. Advantages of Molecular Modification
 Compared to compounds chosen or produced at random, homologs, and analogs are more likely
to have pharmacological qualities similar to those of the prototype.
 Opportunity to obtain pharmaceutically superior products
 Possibility that new drugs will be produced more affordably
 Synthesis that is similar to the prototype's, but takes less time and money
 The information acquired might explain the structure-activity relationship
 Using the same biological assay techniques as the prototype

6. It is the systemic synthesis and evaluation of simpler
analogs of the lead compound. These analogs are
partial or virtual replicas of the prototype drug., which
is a natural product of very intricate chemical
structure.
GENERAL PROCESS: MOLECULAR DISSOCIATION:

7. GENERAL PROCESS: MOLECULAR ASSOCIATION
Molecular Addition
• Addition of Different
Moieties through weak
forces such as electrostatic
attraction & H-bonding
• Methanamide + Mandalic
acid = Methaneamide
mendalate
Molecular Replication
• Addition of identical
moieties through covalent
bond
• p-chlorophenol + p-
chlorophenol = fenticlor
Molecular
Hybridization
• Association of different or
mixed moieties through
covalent bonding.
• Paracetamol + Aspirin =
Benorilate

8. Special Process of Molecular Modification
It usually different types :
• Ring closure/opening
• Lower/higher homologs
• Introduction of double bonds
• Introduction of chiral center
• Introduction, removal or replacement of bulky groups
• Isosteric Substitution
• Change of orientation of certain groups
• Introduction of Alkylating moiety
• Modification towards inhibition or promotion of various electronic states

9. Introduction of double bond
 Presence of doble bond in a drug makes the drug rigid
 Drug without double bond ( having single bond) make the compound flexible.
 Due to this addition or removal of double bonds, activity may loss or increase.
 This makes easier for the drug to fit into the active site.

10. • A chirality center is characterized by an atom
that has four different groups bonded to it in
such a manner that it has a non-
superimposable mirror image.
• Drugs binds and exerts its effects through
binding to specific receptor. As receptors are
stereoselective introducing chiral center
during drug design can alter drug’s activity.
• Example: (-)-adrenaline is twice as potent as
(+) adrenaline.
INTRODUCTION OF CHIRAL CENTER

12. Alkylating Agents:
An alkylating agent is used to treat in cancer that attaches an alkyl group to DNA.
The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen
atom of the purine ring.
Alkylating agents keep the cell from reproducing ( making copies of itself ) by
damaging its DNA.
These drugs work in all phases of the cell cycle & are used to treat many different
cancers, including cancers of the lung, breast, ovary as well as leukemia etc.

13. Mechanism of action:
Alkylating agents
From highly reactive carbonium ion
Transfer alkyl group to nucleophilic sites on DNA bases
Results in
Cross linking abnormal base pairing DNA strand breakage
decrease cell proliferation

14. DRUG
DISCOVERY
Drug discovery is the process through which
potential new therapeutic entities are identified,
using a combination of computational ,
experimental , translational ,and clinicals models.
Johan Ernst Oswald Schmiedeberg is known as
the father of the drug discovery.
Drug Discovery
Process
1
Hit
Identification
2
Lead
Generation
3
Lead
Optimization
4
Target
Validation

15. LEAD COMPOUND
Chemical compound that has pharmacological or biological activity
likely to be therapeutically useful
Also called developmental candidates, because the discovery and
selection of lead compounds occurs prior to preclinical and clinical
development of the candidate.

16. LEAD OPTIMIZATION
Molecules are chemically modified and subsequently characterized in order to obtain
compounds with suitable properties to become a drug.
Leads are characterized with respect to pharmacodynamic properties such as efficacy
and potency in vitro and in vivo, physiochemical properties, pharmacokinetic
properties, and toxicological aspects.
Once compounds with desirable in vitro profiles have been identified, these are
characterized using in vivo models.

17. LEAD OPTIMIZATION IN THE DRUG DiSCOVERY
PROCESS

18. METHODS OF
LEAD
OPTIMIZATION
Identification and quantification of active molecules
Changing size and shape
Functional group optimization
Homologation
Structural activity relationship
Cyclization of side chain
Rigidification of the structure
Bio Isosterism

19. WHAT IS DRUG
LATENTIATION?
It is the process of purposely
designing and synthesizing a
molecule that specifically
requires bioactivation to a
pharmacology active
substance. Drug latentiation is
synonymous with prodrug
design.
Prodrug is a pharmacologically
inactive derivative of an active
drug and undergoes in vivo
biotransformation to release the
active drug by chemical or
enzymatic cleavages.

20. DRUG LATENTIATION PROCESS WITH EXAMPLE:

21. PURPOSES OF DRUG LATENTIATION
To improve selectivity of action.
To improve ADME (Absorption, Distribution, Metabolism&
Excretion) Profile.
To obtain drug having more desirable properties than the
lead compound in terms of potency, toxicity & specificity.
To obtain marketable alternative drug that can compete with
an existing one.
Exploitation of side effects of existing drug.

22. TYPES OF DRUG LATENTIATION
Several approaches may be used for drug latentiation but
two major ways are followed:
Design the prodrugs where those are bioactivated inside
the cells (intracellularly). Examples of these are anti-viral
nucleoside analogs that must be phosphorylated and the
lipid-lowering statins.
Design the prodrugs where those are bioactivated outside
cells (extracellularly), especially in digestive fluids or in the
body's circulatory system, particularly in the blood.
Examples: certain antibody, gene or virus-directed enzyme
prodrugs used in chemotherapy or immunotherapy.

23. PRO DRUGS
👉Prodrugs are pharmacologically inactive derivatives of active drugs that are
designed to maximize the amount of active drugs that reaches it’s site of action
through manipulation of physiochemical, bio pharmaceutical & pharamocokinetic
properties of drugs.
👉They are converted into active drugs through enzymatic or non enzymatic
reactions within the body.The process is called Drug Latentiation.
👉Properties of ideal prodrugs –
• Pharmacological inertness
• Rapid transformation chemically or enzymatically into it’s active form at the
target site.
• Non-toxic metabolite fragments followed by their rapid elimination.

24. MECHANISM OF ACTION OF PRODRUGS:

25. CLASSIFICATION OF PRODRUGS
Prodrugs can be classified into two types based on their site of conversion into an active
drug.

26. 1 2 3 4
APPLICATION OF PRO DRUGS
PRODRUGS
TO
IMPROVE
PATIENT
ACCEPTABI
LITY
ENHANCING
DRUG
SOLUBILITY
&
SUSTAINED
DRUG
ACTION
ENHANCING
DRUG
ABSORPTIO
N &
DISTRIBUTI
ON
SITE
SPECIFIC
DRUG
DELIVERY

27. ADVANTAGES AND DISADVANTAGES OF
PRODRUGS:
Advantages
1. Reduce adverse effects of drugs
2. Drug can be targeted to the
desired site
3. Synergistic effects can be obtained
without side effects.
4. Give additional biological action as
that of parent drug.
Disadvantages
1. Formation of toxic metabolites.
2. The active doses of two mutual
prodrugs of the same parent drugs
may appear to be same in rats but may
be quite different in clinical
investigations.
3. The prodrugs might consume a vital
cell constituent such as glutathione
during its activation stage which causes
depletion of prodrugs.

28. Concluded into Four
approaches :
History of & Approaches drug discovery
Serendipity
Chemical
modification
Screening
Rational

29. Serendipity:
Serendipity refers to the faculty or phenomenon of finding valuable or agreeable things not sought for. 1928
Fleming studied Staph, but contamination of plates with airborne mold. Noticed bacteria were lysed in the area of
Mold. Amold product inhibited the growth of bacteria . It was the antibiotic penicillin.
Chemical modification:
A Traditional method in which analog of a known active compound, synthesized with a minor
modification, that will lead to improved biological activity.

30. Screening:
Screening is the process by which potential drugs are identified and
optimized before selection of a candidate drug to progress to clinical
trials.Testing a random and large number of different molecules for
biological activity reveals leading compounds. Innovations have led to
the automation of synthesis and testing.
Example: Prontosil is derived from a dye that exhibited antibacterial
properties.
Rational :
It starts with a validated biological target and ends up with a drug that
optimally interacts with the target and triggers the desired biologic
action.

31. Drug Discovery Process and Rational Drug Design

33. IMPORTANCE OF
RATIONAL DRUG
DESIGN
THE MAIN STEP IN A
SUCCESSFUL DRUG
DISCOVERY PIPELINE IS
THE IDENTIFICATION OF
SMALL POTENT
COMPOUNDS THAT
SELECTIVELY BIND TO THE
TARGET OF INTEREST WITH
HIGH AFFINITY.
. IT RELIES ON PRIOR
KNOWLEDGE OF THE
STRUCTURE, FUNCTION,
AND MECHANISM OF THE
TARGET,
THEREBY AVOIDING
RANDOM TESTING OF
THOUSANDS OF
MOLECULES.

34. Some Factors that Contribute to Drug Discovery
⮚ Advances in molecular biology and high-throughput screening.
⮚ Demand fundamentals:
i) aging populations
ii) consumer demand for quality health care.
iii) expanded access and universal health care
iv) new break-through technologies
v) consumer awareness of the quality of nutrition and supplements
⮚ Supply fundamentals
i) hospital downsizing
ii) insurers reluctance to pay high reimbursements
iii) transition to outpatient procedures
iv) disease management
v) global management
⮚ Regulation and the cost-effectiveness of drug discovery

35. WHAT IS
ANTIMETABOLITE ?
A drug that possesses a remarkably close
chemical likeness ( mimic) to the normal
metabolite is called an antimetabolite. In
other words, antimetabolite is a chemical
which is similar in structure to the
metabolite with which it interfere and
inhibits its use.

36. Antimetabolites Show Their Activity in Two Ways
✔Product with incorporated Antimetabolite
✔Non-functional
Substrate Antimetabolite
✔Block the activity to proceed
✔No Product
1 2

37. 1.Base Analogues: Structures in nucleic acids that can behave as nucleobase
replacements. This suggests that these molecules are structurally close enough
to DNA's fundamental components to be substituted for them.
Purine Analogues – The bigger bases adenosine and guanosine, which are
integrated into DNA as adenosine and guanosine, have a similar structure to
metabolic purines. Examples: Azathioprine, Thiopurines, and Fludarabine
Pyrimidine Analogues – It has the same structure as metabolic pyrimidines, the
smaller bases like cytosine and thymine that are integrated into DNA. Examples:
5-Fluorouracil, Gemcitabine, and Cytarabine
2.Anti-folates : Chemicals that inhibit the activity of folic acid (vitamin B9),
which is required for the formation of DNA and the growth of cells. Example
Methotrexate and Aminopterin.
ANTIMETABOLITES ARE CLASSIFIED
BASED ON STRUCTURAL

38. Antimetabolites Principal Cell Targets
6-Mercaptopurine De novo purine synthesis, GTP depletion,
DNA incorporation
6-Thiopurine DNA incorporation
Methotrexate Dihydrofolate reductase
5-Fluorouracil Thymidylate synthase, RNA synthesis
Fludarabine Ribonucleotide reductase
Cytosine arabinoside DNA polymerase
Gemcitabine DNA and RNA incorporation, CTP
synthase
Antimetabolites and Their Principal Cell Targets

39. Cancer Treatment: Antimetabolites are group
of anticancer agents that exert their cytotoxic
effects by interfering with the DNA synthesis.
Some of the important drugs from this class are 5-
fluorouracil
(5FU), capecitabine, floxuridine, cytarabine etc.
These molecules are pyrimidine or purine
analogues with altered chemical groups and
induce cell death during the S phase of cell growth
when incorporated into RNA and DNA or inhibit
enzymes needed for nucleic acid production
FUNCTIONS OF
ANTIMETABOLITES

40. Antifolates Inhibit Formation of Tetrahydrofolate
DNA
Methotrexate
Tetrahydrofolate

41. 2. As Antibiotics : Antimetabolites may also be
antibiotics, such as sulfanilamide drugs , which
inhibit dihydrofolate synthesis in bac by competing
with para- aminobenzoic acid (PABA). PABA is
required to produce folic acid which acts as a
coenzyme in the synthesis of purines and
pyrimidines , the building blocks of DNA.

42. Therapeutic Importance of Anti-metabolites
Treatment of several forms of human cancer : 6-Mercaptopurine, 5-Fluorouracil
Anti-folate as a treatment of human cancers : Methotrexate, Trimethoprim
Treatment of acute leukaemia : 6-mercaptopurine and 6-thioguanine
Immunosuppressive in organ transplant : Azathioprine
Treatment of gout and hyperuricemia : Allopurinol
Acyclovir for treatment of herpesvirus infection
Treatment against microbes : Sulphanilamide Actinomycin-D

43. Other use of Antimetabolites
1.Antimetabolites can be used in Infectious Diseases, Inflammation & Immunology
2. Antimetabolites can be used in Dermatology.
3. Antimetabolites can be used in Systemic Antineoplastic Treatments for Cardiologists.

44. Enzyme Inhibitor
An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity.
An enzyme inhibitor stops ("inhibits") this process, either by binding to the enzyme's active site
(thus preventing the substrate itself from binding) or by binding to another site on the enzyme
such that the enzyme's catalysis of the reaction is blocked.

45. Reversible Inhibitor Irreversible Inhibitor

46. Iodoacetate