AND
DEVELOPMENT
DEFINITIONS
• What is drug?
• Discovery vs Invention
• Drug discovery is the process of identifying and characterizing
molecules with the potential to safely modulate disease, with a goal to
bring medicines that can improve the lives of patients.
• Development Phase: compounds are tested for safety and efficacy for
one or more clinical indications, in suitable formulations and dosage
form.
Importance in healthcare and pharmaceutical
industries
• New Diseases
• Previously untreatable disease
• Different metabolism
• Low cost drugs
• Drug resistance
IND NDA
Comparison
Drug discovery stages
Lead
Target Target Validation Lead
Identification
Identification • Knock out animal
Optimization
High throughput
• Cellular and models screening Medicinal chemistry
molecular biology • Proteomics Natural product Parallel synthesis
• Genomics
• Proteomics
• Nucleic acids and screening Design of focused
compound libraries
Preclinical
antibodies Virtual screening
and clinical
• Bioinformatics Molecular modeling,
• Structural biology NMR based screening
and structural Combinatorial
QSAR phase
genomics screening Structure based
design
Compound library
design In-vivo pharmacology
Structure based [Link] and
design toxicology
Target Identification
• Target: A therapeutic target is in general a macromolecule (typically a protein),
which may cause or be associated with a particular disease, that can be
modulated by a therapeutic agent in a measurable way.
• Proteomics: It is the process of separation and characterization of all the
proteins of a biological system. Target identification with proteomics can be
performed by comparing the protein expression levels in normal and diseased
tissues.
• Genomics: it is the study of all of a person's genes (the genome), including
interactions of those genes with each other and with the person's environment.
• Bio-informatics: is a scientific sub discipline that involves using computer
technology to collect, store, analyze and disseminate biological data and
information, such as DNA and amino acid sequences or annotations about
those sequences.
Target validation
• It involves demonstrating the relevance of the target in a disease
process and druggability.
• Validation techniques range from in vitro tools through the use of whole
animal models, to modulation of a desired target in disease patients.
• The careful validation of target proteins will reduce the failure rate and
increase the overall efficiency of the drug discovery process.
Knock out animal models (loss of function) and knock in animal models
(gain of function)
Proteomics
Antisense nucleic acids and antibodies
Structural biology and structural genomics
Lead Identification
• Identified compounds which interact with the target protein and modulate its
activity are called leads.
• Lead generation approaches:
1) Newer techniques:
▪ Molecular modeling- docking, CADD https://
[Link]/Sux91FJ3Xe8?si=AiOijcL6KBDnsy5P
▪ Combinatorial chemistry
▪ Biotechnology
▪ Immuno-pharmacology
2) Older techniques:
▪ Random screening
▪ Ethnobiological approach
Lead Identification
• Screening of lead compound
1) Virtual screening (in-silico screening/ docking models)
▪ Target based virtual screening
▪ Ligand based virtual screening
2) Real screening:
▪ High throughput screening: https://
[Link]/Q1GFtrm8hg4?si=B6SGdoqniAo_pzM9
Lead Identification
If the hits fulfill following criteria are regarded as leads:
• Pharmacodynamic properties: efficacy, potency and selectivity- in
vitro and in-vivo
• Physicochemical properties: Lipinski’s rule of five, water solubility and
chemical stability
• Pharmacokinetic properties
• Chemical optimization potential
• Patentability
Lead Optimization
• During the lead optimization, small organic molecules are chemically
modified and subsequently pharmacologically characterized in order to
obtain compounds with suitable pharmacodynamic and pharmacokinetic
properties to become a drug.
• Steps of lead optimization:
1. Identification of the pharmacophore
2. Functional group modification
3. SAR establishment
4. Structure modification to increase potency and therapeutic index
5. QSAR
6. Molecular graphics based drug design
Preclinical Development
Preclinical studies are performed in animals to define pharmacological and
toxicological effects not only prior to initiation of human effects but throughout
clinical trials.
Both in vitro and in vivo studies can contribute to this characterization.
Objectives of preclinical testing:
▪ To decide that it is reasonably safe to proceed with human trials of the drug.
▪ To identify criteria for evaluating safety in humans
▪ Identify, describe and characterize hazards
▪ Establish dose-response estimation of pharmacology and toxic effects
▪ Assessing pharmacokinetics (PK) and pharmacodynamics (PD)
▪ Assessing toxicity studies: in vitro and in vivo
Regulatory considerations: GLP
Preclinical Development
• Study in two species (rodent and non-rodent) is required to check
species difference in responses.
• Types of preclinical testing:
ꙩ Short term animal studies
ꙩ Long term animal studies
For Phase I Clinical Trials
• Systemic Toxicity studies
(i) Single dose toxicity studies
(ii) Dose Ranging Studies
(iii) Repeat-dose systemic toxicity studies of appropriate duration
• Male fertility study
• In-vitro genotoxicity tests
• Relevant local toxicity studies with proposed route of clinical application (duration
depending on proposed length of clinical exposure)
• Allergenicity/Hypersensitivity tests (when there is a cause for concern or for
parenteral drugs, including dermal application)
• Photo-allergy or dermal photo-toxicity test (if the drug or a metabolite is related
to an agent causing photosensitivity or the nature of action suggests such a
potential)
For Phase II Clinical Trials
• Provide a summary of all the non-clinical safety data (listed above)
already submitted while obtaining the permissions for Phase I trial, with
appropriate references.
• In case of an application for directly starting a Phase II trial - complete
details of the non-clinical safety data needed for obtaining the permission
for Phase I trial, as per the list provided above must be submitted.
• Repeat-dose systemic toxicity studies of appropriate duration to support
the duration of proposed human exposure
• In-vitro and In-vivo genotoxicity tests.
• Segment II reproductive/developmental toxicity study (if female patients
of child bearing age are going to be involved)
For Phase III Clinical Trials
• Provide a summary of all the non-clinical safety data (submitted while
obtaining the permissions for Phase I and II trials)
• In case of an application for directly initiating a Phase III trial - complete details
of the non-clinical safety data needed for obtaining the permissions for Phase I
and II trials.
• Repeat-dose systemic toxicity studies of appropriate duration.
• Reproductive/developmental toxicity studies .
• In-vitro and In-vivo genotoxicity tests.
• Segment I (if female patients of child bearing age are going to be involved), and
Segment III (for drugs to be given to pregnant or nursing mothers or where
there are indications of possible adverse effects on foetal development).
• Carcinogenicity studies (when there is a cause for concern or when the drug is
to be used for more than 6 months)
Clinical Research Process
Clinical research refers to medical research on human subjects.
The subjects of clinical research are mainly classified into the following
four categories.
• Investigation of the cause of injury/ illness
• Understanding of clinical conditions
• Improving or validating the effectiveness of methods for preventing
injury/ illness.
• Improving or validating diagnostic or treatment methods in medicine.
There are two main types of clinical trials----
• Observational Clinical trials: these trials does not involve treatments
or drugs. Researchers observe participants by monitoring their health
over a period of time. These studies provide researchers with data
that advances our understanding of Parkinson’s and how to treat the
disease.
• Interventional Clinical trials: These trials test the safety and
effectiveness of a candidate drug, therapy or experimental treatment.
Within these broad categories, trials also can be classified as follows.
• Treatment trials: Generally involves an intervention such as medication,
psychotherapy, new devices or new approaches to surgery or radiation therapy
• Prevention trials: looks for better ways to prevent disorders from developing or
returning. Different kinds of prevention research may study medicines, vitamins,
vaccines, minerals or lifestyle changes.
• Diagnostic trials: refers to the practice of looking for better ways to identify a
particular disorder or condition.
• Screening trials: aims to find the best ways to detect certain disorders or health
conditions
• Quality of life trials: explores ways to improve comfort and the quality of life for
individuals with a chronic illness.
• Genetic studies: aims to improve the prediction of disorders by identifying and
understanding how genes and illness may be related.
Terminology
• Clinical research protocol
• Sponsor
• Investigator
• IRB/IEC
• Informed consent
• Investigator brochure
Study design
• Uncontrolled trials
• Controlled trials:
• Randomized controlled trials
• Types of blinding
Phase 0 trial (Micro-dosing studies)
Phase 1 (Human Pharmacology)
Phase 2 (Therapeutic exploratory)
Phase 3 (Therapeutic Confirmatory)
Phase 4 (Post marketing
surveillance)
Summary
Challenges in Drug Discovery and
Development
•High costs and long timelines
•Regulatory hurdles
•Emerging technologies and trends
Future Directions
•Personalized medicine
•Biologics and gene therapies
•AI and machine learning in drug discovery
