Document includes description of complete Drug Discovery process, right from Research and Development phase,Pre-clinical trials,IND Submission,Clinical trials, NDA Submission.Also we have added Limitations and Recent Advances in Drug discovery process.At last we have added Ai based softwares which will prove beneficial for Future Researchers.

1. Drug Discovery Process:
Concept to Medicine
Presented by:
Sumit Devkar
F.Y.M.Pharm (Pharmacology).
Roll.no. - 05
Guided by:
Prof. H.J. Pagar
Professor and HOD
Department of Pharmacology
PDVVF’s College of Pharmacy,
Ahilyanagar.

2. Content
Introduction
Stages of Drug discovery
Initial Drug Discovery
Target Identification
Target Validation
Lead Identification
Lead Optimization
Preclinical trials
IND submission
Clinical Trials
Phase – 0
Phase – 1
Phase – 2
Phase – 3
NDAApplication
Phase – 4 (PMS)
 Recent Advances in
Drug Discovery

3. Introduction
• Drug Discovery Process is a Systematic Inventive process of
identifying potential new drugs, evaluating their safety and
effectiveness, and ultimately bringing them to market as a
medicine.
• It takes around 12-25 Years.
• Drug Discovery process can cost anywhere from $1 billion to
over $2.6 billion USD.
• Drug discovery requires a multidisciplinary approach, involving
experts from various fields, including biology, chemistry,
pharmacology, and medicine.
• Complexity and challenges involved in drug discovery results in
high development costs, which can be a barrier to innovation.
• Over the decades,pattern for drug discovery and drug
development process has evolved, but there was still high
degree of trial and error involved in the process,which is now
overcome due to introduction of AI in Drug Discovery.

5. STAGES OF DRUG DISCOVERY
 Initial Drug Design : (R&D)
 Target identification
 Target Validation
 Lead Identification
 Lead Optimization
 Pre-clinical Trials
 Pharmacokinetics studies (PK)
 Pharmacodynamics Studies (PD)
 Toxicology studies
 IND Submission
 Clinical Trials
 Phase – 0
 Phase – 1
 Phase – 2
 Phase – 3
 NDA Submission
 Phase – 4 (PMS)

7. A. Initial Drug Discovery
 Drug discovery is the process of discovering new chemical entity as a
potential therapeutic agent. (3-6 Years)
 Also called as Research and Development Phase.
 A chemical moiety is newly identified for its Therapeutic effect against
desired Disease.
 Various sources like academic research, clinical works and commercial
sector help in the identification of appropriate disease target
 Chosen target is then used by the pharmaceutical industry to identify
molecules for making acceptable drugs.
 5-6 Candidates from millions of compounds are selected at end of this step
which shows promising therapeutic effect.
 It involves following Key Steps:
I. Target identification
II. Target Validation
III. Lead identification
IV. Lead optimization

8. 1.Target Identification
Defining intervention points for therapies
• This process involves finding the targets that causes or leads to the disease.
• A target can be specific protein/enzyme/receptor which is an important part of disease
pathogenesis.(1-2Years)
• Sometimes it may be also DNA or RNA.
• Specificity of selected target in Disease pathway can offer safer treatment.
• A good Target should be accessible by drug molecule.
• During this target identification stage, researchers must determine whether the target
is efficacious and safe to be used as a target.
• Majority of Drug Targets are:
Target Frequency to be used as
target
G-protein coupled receptors 45%
Enzymes 28%
Hormones 11%
Ion channels 5%
Nuclear receptors 2%

9. 1) Cellular & molecular biology:
CMP aims todiscovers new genes and protein.
2) Genomics:
• Structural Genomics:
Focuses on determining the three-dimensional (3D)
structure of every protein.
• Functional Genomics:
Discuss about biological functions of genes.
3) Proteomics:
• Large scale study of protein & their function.
• It is the study of the complete set of proteins
along with its separation and identification.
4) Bioinformatics:
• Extensive analysis of biological data using
computers, for the purpose of enhancing
biological research.

10. 2.Target Validation
Confirming Therapeutic Relevance
• Target validation Confirms that molecular target is directly involved in a
disease Pathology, also modulating its activity (i.e., inhibiting, activating,
or degrading it) will produce a desired therapeutic effect.
• It helps to reduce the failure rate of Drug Discovery.
• Requires 6-8 Months.
• Target Validation can by done by various methods:
1) Targeted Protein Degradation (TPD).
2) Overexpression Studies.
3) Gene Knockout.
4) Gene Knockdown.
5) Organ-on-a-Chip Models.
6) In Silico Trials.
 ORGAN ON A CHIP : A multi channel 3-d microfluidic cell culture chip that simulates
the activities, mechanics and physiological response of entire organs and organ systems.

11. 3.Lead Identification
Screening for Promising Candidates
• A structured approach to simultaneous synthesis, efficient identification and screening
large number of potential drug candidates in drug discovery . (8months -2Years)
• A lead compound is generally defined as a new chemical entity that could potentially
be developed into a new drug by optimizing its beneficial effects and minimizing side
effects.
Rapidly tests thousands of compounds
to identify those with desired biological
activity.
Random Screening
All compounds including synthetic
chemicals, natural products of plant,
marine and microbial origin from a
given series are tested.
In silico lead discovery
Drug discovery basedd on Computer
system.
Combinatorial chemistry
rapidly synthesize large numbers of
diverse chemical compounds
High-throughput screening
Methods For Lead Identification

12. 4.Lead Optimization
Enhancing Drug Like Properties
• It is process of refining these initial promising molecules to enhance their desirable
properties and minimize unwanted ones,(1-3Years)
• Often described as a "Design-Make-Test-Analyze" (DMTA) cycle.
• Lead Optimisation transforms Lead into viable drug candidates for preclinical and
clinical trials.
 Aims of Lead Optimisation:
1) Optimize Pharmacokinetics (ADME):
2) Enhance Selectivity:
3) Reduce Toxicity:
4) Establish Intellectual Property:Optimized compound gains strong patent potential.
 Key Techniques and Strategies:
1)Medicinal Chemistry- SAR,QSAR,3D-QSAR
2)High-Throughput Screening (HTS)
3)Artificial Intelligence (AI) and Machine Learning (ML)

13. B.Pre-Clinical Development
• Preclinical trials are carried out on animal
models (2-5 Years).
• Nowadays transgenic animal models are
used.
Studies conducted here are governed by
IAEC
 Acute and chronic toxicity studies:
Uses single or repeat doses.
Absence of toxicity  safety
The toxicity studies to be conducted for a
drug depends upon it's intended clinical
usage. As noted earlier, a drug meant for
Benign Prostatic Hyperplasia is never going
to be used in women.
 Genotoxicity studies:
test for gene mutation.
chromosomal damage.
 Carcinogenicity:
 Fertility study:
 Teratogenecity:
Rodents - mouse, rat, guinea pig, hamster, rabb
Non rodent- cat,dog,monkey,chicken

14. C.IND Submission
• An Investigational New Drug (IND) application is submitted to USFDA to grant
approval for use of an investigational drug in Humans.
• The IND application allows the FDA to review the safety and efficacy of new
treatments before they are tested in humans.
• FDA Scrutinize documents and grant permission to conduct clinical trials.
 Types of IND Applications:-
 Commercial IND: Submitted by sponsors who intend to market the product
upon FDA approval.-
 Research (Non-Commercial) IND: Submitted by researchers who want to
study an investigational product with/without intending to market it.
 Key Components of an IND Application:-
 Preclinical Data:
 Manufacturing Information:
 Clinical Trial Protocols:

15. D.Clinical Development
• Testing of investigational drug in Humans is called as
Clinical Development.(6-7 Years)
• Classically, clinical trials have been described as Phase I, II,
III or IV, but recently FDA has introduced Phase O to these
Stages.
• Food and Drug Administration (FDA): Oversees clinical
trials, ensuring compliance with regulations and participant
safety.
• Institutional Review Boards (IRBs): Review and approve
trial protocols, protecting participant rights and welfare.
• Clinical trials are conducted in a controlled environment to
ensure reliable results.
• Individual can get free of cost Quality treatment for certain
disease.

16. 1. Phase – 0 Studies
Microdosing Studies
• Known as First in human trial.
• Involves 10-15 Subjects.
• A single sub-therapeutic dose of the study drug is
administered to human volunteers and the drug tracked all
over the volunteer's system.
• Microdose : 1/100th of the dose of a test substance,
calculated to yield a pharmacological effect.
• Principal objective is to ensure that the drug reaches the
required sites and not elsewhere.
• Actual patient exposure to the drug in a Phase 0 study is very
brief, often just a single dose or a few doses over up to 7
days.
• entire process from planning to study completion takes
approximately 10 to 14 months.

17. 2. Phase – 1 Studies
Human Pharmacology and safety
• In this phase drug is tested on 20 – 80 healthy subjects.
• Phase -1 Trials conducted in specialized centers where
monitoring of various body functions is possible.(Several
months to 1 year.)
• when the starting dose is much below the clinical dose and
gradual increase of dose is achieved even beyond the clinical
dose.
• Repeat dose studies are also undertaken, if the drug is one
which is expected be used in such a fashion.
• Phase 1 studies can be open-label or blinded.
• maximum tolerated dose is assessed.
• Close monitoring and Regular assessments of subjects.
• Approximately 70% of drugs move to the next phase.

18. 3. Phase – 2 Studies
Therapeutic exploration and dose ranging
o Phase 2 this phase is carried out on patients
(Sample size : 100 -300) suffering from the target
disease. (Up to 2 years.)
o Time when drug reaches this phase, it's safety
has been established in humans, Hence Phase 2
studies are generally safer than Phase I studies.
o This phase mainly explores efficacy.
o Drug development process for a new drug often
fails in phase II trials when the drug candidate
does not work as Intended, or has toxic effects.
o Approximately 33% of drugs move to the next
phase.

19. 4. Phase – 3 Studies
Therapeutic confirmation/ comparison
• Phase III studies are the most critical studies that establish the
marketability of the new drug.(1 to 4 years).
• There are many designs that could be used for these studies,
prospective, randomized comparative, double blinded studies.
• Placebo controlled studies are no longer ethically acceptable,
barring a few select conditions.
• Sample size : Hundred to Thousands.
• This phase should compare the new drug with the best
available therapy in the market.
• Regulatory requirements and the available resources in terms
of subjects, time and money.
• Approximately 25-30% of drugs move to the next phase.

20. 5. NDA Application
Biologics License Application (BLA)
o FDA Review and grant the marketing permission to Investigational drug.
o Purpose of New Drug Application (NDA) is to demonstrate that a drug is safe and
effective for its intended use in the population studied.
o A drug developer must include everything about a drug-from preclinical data to
Phase 3 trial data in NDA.
 Developers must include
1. Clinical results,
2. Proposed labeling
3. Safety updates
4. Drug abuse information
5. Patent information
6. Any data from studies that may have been conducted outside the United States
7. Institutional review board compliance information
8. Directions for use
 Once FDA receives an NDA, If it is complete, the review team has 6 to 10 months
to make a decision .
 Each member of the review team conducts a full review of his or her section of
the application.
 FDA inspectors travel to clinical study sites to conduct a routine inspection.

21. 6. Phase – 4 Studies
Post marketing survillance studies
• Safety of the drug continues to be studied, right from phase I
to long after the drug has been marketed.
• Pharmacovigilance is the science and activities relating to the
detection, assessment, understanding and prevention of
adverse effects or any other possible drug-related problems.
(WHO)
• Pharmacovigilance system works after the drug is approved
and marketed and continues till drug is in market.
• Post marketing studies therefore reveal more adverse effects
than those are seen in the trials.
 Periodic Safety Update Reports :
6 monthly for first two years
Annually for the next two years

22. D. Limitations
Poor Understanding of Disease Mechanisms: For many diseases, especially
complex ones.
Poor Predictability of Animal Models: Animal models often fail to accurately
mimic human disease pathology and drug response due to physiological, genetic,
and immunological differences.
High development costs: Developing a new drug from discovery to market
approval can cost anywhere from $1 billion to over $2.6 billion USD, including the
cost of failed projects.
High Failure Rates: Only about 1 in 10,000 compounds entering the discovery
pipeline eventually makes it to market, and only about 1 in 5 drugs entering human
trials gets approved.
Global Regulatory Variability: Different countries have distinct regulatory
frameworks, making it challenging for multinational pharmaceutical companies to
navigate approval processes across various markets.
Stringent Regulatory Requirements: Regulatory agencies (like FDA in the US,
EMA in Europe, CDSCO in India) have extremely Strict standards for drug safety
and efficacy.

23. E. Recent Advances
 Artificial Intelligence (AI) and Machine Learning (ML) as Core
Drivers:
o identify novel, "druggable" targets.
o Helps to formulate suitable formulation
 Drug Repurposing: AI can rapidly identify new therapeutic uses for
existing, approved drugs, offering a faster and less risky path to new
treatments.
 Organ-on-a-Chip Systems: miniaturized, lab-grown human tissues and
multi-organ platforms offer more physiologically relevant models for
drug efficacy and toxicity testing.
 Gene Editing Tools(e.g., CRISPR-Cas9): offering the potential to correct
or replace defective genes, providing curative treatments for a wide range
of genetic disorders (e.g., sickle cell disease, beta-thalassemia).
 Advanced Drug Delivery Systems: nanoparticles, Implantable Devices,
Microneedle Patches,TDDS.
 Technology: genomics, proteomics, high throughput screening and
structure-based drug design

24. Recently developed
AI tools
in Drug Discovery

25. : Target Prediction tool
http://www.swisstargetprediction.ch/
Triclosan : Broad spectrum antimicrobial agent

26. Protein Data Bank:
https://www.rcsb.org/

27. CAVER : Binding Site Prediction tool
https://caver.cz/

28. Flare: Ligand Designing tool
https://cresset-group.com/software/flare

29. SwissDock : Docking score analysis
https://www.swissdock.ch/
Haemoglobin

30. ADMETlab 3.0 : Pharmacokinetics Analysis
Edoxaban : Anticoagulant drug
https://admetlab3.scbdd.com/

31. GastroPlus :Pharmacokinetics Analysis
https://www.simulations-plus.com/software/gastroplus/

32. PROTOX : Toxicity Prediction tool
https://tox.charite.de/protox3/

33. Tamoxifen : Selective Estrogen receptor modulator (SERM)

34. SwissSimilarity : HT Ligand based Virtual screening tool.
Salbutamol
http://www.swisssimilarity.ch/

35. https://formulationai.computpharm.org/
Formulation Ai : Drug Formulation Designing tool

38. FormulationAI : Pharmaceutical formulation prediction platform
https://formai.geinforce.com/

39. Other Databases
 Protein Databases
1.ProteinDataBank(PDB)
2.Zinc Database, Zinc15Database
3.ChEMBLJ
4.ChemforExcel
5.BindingMOAD(Mother Of All Database)
6.PDBbindSTITCH,SMPDB
 Molecular Analogues Searcher:
1.Swisssimilarity
2.Modeller
3.I- TASSER
LOMETS
4.SWISS-MODEL
5.SWISWS-MODELRepository
 Binding site prediction tools
1.MED –SuMu
2.Caver
3.FINDSITE
4.Sc-PDB
5.Pocketome
6.3DLigandSite
7.metaPocket
8.PocketAnnotate
 Molecular Docking
1.Autodock
2.Schrodinger
3.Molsoft
4.DOCK
5.GOLD
6.SwissDock
7.DockingServer
8.1-ClickDocking
9.iGEmdock
 ADME Toxicity
1. VolSurf
2. Gastroplus
3. MedChemStudio
4. ALOGPS
5. Metrabase
 Digital Twins: In vivo simulators/Virtual models
of biological system.
 Arctoris: Fully automated , Robotics driven Drug
discovery.

40. References
1. Padmaja Kore, Subhash Bodhankar et al. “Principles of Drug Discovery”,
First Edition ,Pharma Career Publication.2022,
2. RICK NG et al.“DRUGS :From Discovery to Approval”, Second Edition ,
A John Wiley & Sons, Ltd. Publication,2009,, ISBN 978-0-470-19510-9
3. Sachin Itkar, Dr. N.S. Vyawahare et al. “Drug Regulatory Affairs”,First
edition, Nirali Prakashan.2020
4. Dr. R.B Ghooi et al. "Principles of Clinical Research", First edition, Nirali
prakashan, 2013.
5. Neal G. Simon , Mukund s. Chorghade et al. “Drug Discovery &
Development “, First Edition,2006, John Wiley & Sons, Inc.
Publication,2012
6. Sandy Weinberg et al. “Guidebook for drug regulatory submissions”. A
John Wiley & Sons. Inc. Publication.2014
7. Douglas J. Pisano, David Mantus et al. “FDA Regulatory Affairs: a guide
for prescription drugs, medical devices, and biologics”,CRC Press
Publication, 2004
8. Leon Shargel and Isader Kaufer et al. “Generic Drug Product Development,
Solid Oral Dosage forms”, Vol.143, Marcel Dekker series Publication.
2005,

41. Thank
You..!!