1) The process of bringing a new medicine from initial discovery to patient use (molecule to medicine) is a long, complex, and expensive process involving target identification, preclinical testing, clinical trials, and regulatory review and approval. 2) Preclinical testing involves evaluating a molecule's pharmacokinetics, pharmacodynamics, safety, and toxicity in cell and animal studies. Positive preclinical results allow filing an Investigational New Drug (IND) application to begin human clinical trials. 3) Clinical trials are conducted in four phases to evaluate a drug's safety, efficacy, side effects, and optimal dosing in humans. The entire development process from discovery to approval takes 8-12 years and costs over $1

1. Molecule to medicine
Dr.Meharban , MSc, Ph.D.
Assistant Professor, Department of Pharmacology
Vydehi Institute of Medical Sciences & Research Centre
PHARMAQUEST-2021

2. Molecule Medicine
Bench….. ….Bed

3. Introduction
• The drug discovery and development process (i.e
molecule to medicine)
– Discovery research
– Preclinical testing
– Investigational new drug (IND) applications
– Completed clinical testing before marketing approval from
the FDA.

4. Introduction
• The overarching goal
– More efficient
– Safer treatments to the patients
– Quickly as possible after a thorough medical evaluation
• Very lengthy, long duration, involves multi discipline
people to bring a medicine from molecules discovery
• Very expensive with lot of uncertainty and failures

5. Site
Selection
Molecules to medicine: Process
Target identification:
Choose a molecule in the body to
target with a drug; often a protein
or receptor
Target validation:
Test the target and confirm its role
in the disease pathology
Lead generation:
Find lead compound that could
become a drug through medicinal
chemistry optimization
Early safety testing:
Initial tests on lead compounds,
including pharmacokinetics, by
experiment and/or computer
modelling assess the safety risk
Lead optimisation:
Alter the structure of lead
candidates to improve properties;
this may include formulation,
delivery mechanism and scale-up.
Discovery research Preclinical research Clinical research Regulatory review
& approval
Pharmacokinetic study:
Asses the exposure across preclinical species
and derive the pharmacokinetic parameters
Pharmacodynamic study:
Confirm the efficacy in relevant disease
model in preclinical species
Chemistry, manufacturing and
control( CMC):
Robust chemical synthesis in place to supply
large qty of drug substance
Identified suitable formulation to convert
drug substance into drug product for IND
enabling studies and clinical testing
Safety and toxicology evaluation: To
assess the safety of preclinical candidate in
rodents and non rodents to build body
evidence to take compound for human
testing
Clinical trial exceptions (CTX)
applications
File CTX with appropriate authorities before
clinical testing can begin.
Phase 1 clinical trial
Initial human testing in a small group of
healthy volunteers.
Phase 2 clinical trial
Test in a small group of patients.
Phase 3 clinical trial
Test in a large group of patients to show
safety and efficacy.
Marketing authorisation
application
Apply to appropriate authorities
for approval.
Manufacturing
Begin full-scale production.
On-going studies and
Phase 4 trials
Continuing monitoring and
checking of the drug in use.

6. The essence of Drug Discovery
6
Safe
Effective
Affordable
Profitable
Globally
relevant
Sustainable
Cost
effective
Potent
Safe
Patentable
Hospital Bed
Lab Bench
De-risk
Increase
Probability
of
Success

7. Drug Discovery : timelines
1 Drug
Approve
d
Lead Opt
1000 – 5000
compounds
Pre-Clinical
5-20 compounds Clinical Trials
2-3 compounds
FDA Review
Expenses
~8-12 years
1-3 years
6-10 years

8. Molecule generation
– Random Screening
• HTS - using large compound collection in high throughput mode
– Molecular Manipulation
• Modification existing drug or leads natural product
– Molecular Designing
• Structure based design using crystal bound ligand structure or using enzyme
substrate or natural agonist of receptor or modification natural
neurotransmitter
– Drug Metabolites
• Knowledge based modification metabolites
– Serendipity
• Identification lead by accident, e.g. Viagra

9. Lead generation examples
Natural product source
Lead Drug
Lead Drug
Drug
Drug
Rational design using 3D- structure of enzyme

10. Lead optimization- fine tuning of properties
• Optimizing chemical lead for clinical trial is commonly referred
to as lead optimization
• The refinement in structure is necessary in order to improve
• Potency
• Oral Availability
• Selectivity
• pharmacokinetic properties
• safety

11. Hameed P., et al. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat Commun 6, 6715 (2015)
MMV253: Optimized lead from HTS hits
MMV253 is completed phase-1 study and entering phase-2 trial

12. In-vitro studies
• Drug affinity: Ability of drug to bind to its biological target (receptor,
enzyme, transport system, etc.)
• Selectivity- Drug should bind to specific receptor site on the cell (eg.
Atenolol)
• Solubility and permeability: Helps to assess the drug absorption
• Metabolism and transporter studies: Asses the metabolic stability and
elimination characteristic of molecules
• Off –target selectivity testing : Screening of molecules against various
secondary pharmacology targets ( Cardiac ion channels, enzymes,
receptor and kinases) to build selectivity and reduce safety risk

13. In vivo studies
• Its experimentation using a whole, living organism.
• Gives information about,
• Pharmacokinetic profile (rodents and non rodents)
Magnitude of pharmacological effect depends
on drug concentration at its site of action.
• Pharmacodynamic profile
Establishes effectiveness of drug in preclinical animal disease model to
demonstrate proof concept
e.g SCID mice for malaria,
NOD mice- Diabetes,
Syngeneic mice tumor model for Cancer
PMID: 30131376

14. Safety and toxicity: IND package
Readout and risk assessment
Cardiovascular safety
• Conscious dog telemetry to assess the effect candidate drug on ECG changes, proarrhythmic
and QT prolongation risk
Genetic toxicity
• Ames test to assess and rule out mutagenic potential drug candidate
• in vitro micronucleus to rule out genetic toxicity in vitro under GLP conditions
• in vivo micronucleus and comet test to rule in vivo genotoxic potential drug candidate if it is
found to be positive under in-vitro conditions
General and Organ
toxicity in rodents and
non rodent species
• 14/28-day repeat dosing of compounds in rats and dog to determinate the no observed adverse
effect level(NOAEL) using clinical observations and histopathological findings
• Helps to study toxicokinetic and calculate therapeutic margins for human clinical trials
• Identification monitorable safety risk( Reversible elevation of liver enzymes)
Respiratory toxicity
• To assess the effect of drug candidate on respiration rates and volumes
Central nervous system
toxicity
• To assess the impact of drug candidate on behaviour, sensory / motor responses and body
temperature and associated risk

15. Investigational new drug application
Preparing for an IND Submission
Proof-of-concept scientific
data
• Should include considerations of product activity, ability to replicate results and a reasonable
explanation how the product will prevent, diagnose, treat or cure disease
A target clinical Indication • Disease indication for which the intended drug developed for the treatment
Animal toxicology data
• Usually obtained in two species that supports the dose, dosing schedule, administration,
and study duration proposed in the clinical protocol
Manufacturing process
• Provides evidence that product is manufactured according to GMP, including analytical
tests results confirming the quality of the product several batches of the product
Stability Information
• Data demonstrating the stability of the drug, under defined storage conditions, or the period of use
for the clinical trial
Clinical plan/ protocol • Clinical trial design to assess the safety and tolerability of clinical candidate in human
Request submitted to the FDA to allow human exposure limit to the experimental drug

16. 16
Phases clinical trials
FDA Phases ICH Types Objectives
Phase I Human
Pharmacology
•Assess tolerance
•Drug metabolism and drug interaction
•Estimate drug activity
Phase II Therapeutic
Exploratory
•Assess use for target indication
•Estimate dosage for subsequent studies
Phase III Therapeutic
Confirmatory
•Confirm efficacy
•Collect information for assessing risk /benefit
relationship to support licensing
•Monitor side effects
Phase IV Therapeutic Use Identify less common adverse effects
Refine dosing recommendations
Refine risk benefit relationship in
general or special populations
Approved for
testing in
human
Submitted for
review and
approval
Approved for
human use
Post Marketing
Surveillance
Pharmacovigilance

17. Pre-IND meeting
IND submission
Pre NDA meeting
NDA Submission
Approval
Stages of FDA Review
Engage regulatory authority (FDA) to seek
opinion on preclinical data package to incorporate into IND
Submission of NDA application post phas-3 outcome
for review and approval for human use
Involve regulatory agency for data review post phase-2b/III to elicit
the response and suggestion for NDA application
Submission of IND package for review, allow human exposure limit
and approval for testing in human
Committee reviews and majority opinion decides approval for
human use
30 day