Drug Design: Discovery, Development and Delivery

1
Drug Design Discovery, Development and Delivery
Regulatory Requirements
Dr. Basavaraj K. Nanjwade M.Pharm.,
Ph.D Associate Professor Department of
Pharmaceutics KLE University BELGAUM
590010 E-mail bknanjwade_at_yahoo.co.in Cell No
0091 9448716277
2
Drug Design
3
Drug Design

• Drug design is the approach of finding drugs by
  design, based on their biological targets.
  Typically a drug target is a key molecule
  involved in a particular metabolic or signalling
  pathway that is specific to a disease condition
  or pathology, or to the infectivity or survival
  of a microbial pathogen.
• Other approaches may be to enhance the normal
  pathway by promoting specific molecules in the
  normal pathways that may have been affected in
  the diseased state.
• In medicine, biotechnology and pharmacology, drug
  discovery is the process by which drugs are
  designed

4
Drug Design

• 1. Rational Drug Design
• 2. Computer-assisted Drug Design (CADD)
• 3. Neural network in Drug Design

5
Rational Drug Design

• The industry now has the research tools to
  pursue rational Drug Design successfully, but a
  new hurdle is being raisedfinding a way to
  generate data and manage our knowledge of disease
  that maximizes the value of that knowledge
• 1. Molecular properties
• 2. Receptor-Based modeling
• 3. Numerical methods

6
Rational Drug Design
Refining the understanding of pathogenesis
7
Rational Drug Design
Investigating complex systems increases knowledge
return
8
Computer-assisted Drug Design (CADD)

• Drug design is a three-dimensional puzzle where
  small drug molecules, ligands, are adjusted to
  the binding site of a protein.
• The factors which affect the protein-ligand
  interaction can be characterized by using
  molecular docking and different quantitative
  structure-activity relationships (QSAR) methods

9
Computer-assisted Drug Design (CADD)
In CoMFA map the colored fields describe how
molecular structure can be modified to increase
biological activity (CoMFA-Comparative molecular
field analysis)
10
Computer-assisted Drug Design (CADD)

• CADD most commonly used tool to model biological
  system is molecular dynamics
• The model of a receptor refined with molecular
  dynamics simulations

11
Computer-assisted Drug Design (CADD)
3D models of membrane receptors can be refined
and validated in a realistic lipid-water-salt
environment using molecular dynamics simulations
12
Computer-assisted Drug Design (CADD)

• Virtual screening is a computational technique to
  find novel drug candidates.
• Data from virtual screening can be used to
  develop predictive models in order to optimize
  ADMET properties of the candidate molecules.
• The ultimate goal of this procedure is to find
  investing lead molecules that are worth for
  further drug research and synthesis.

13
Computer-assisted Drug Design (CADD)
New potent inhibitor for the Human Sirutuin Type
2 enzyme was found using a virtual screening
technique
14
Neural network in Drug Design

• This is the most latest technique being applied
  to discover new drugs. It works on the same
  principles as the neural networks found in the
  human brain.
• This technique makes use of Computer Artificial
  Intelligence, whereby a computer learns by
  itself, how to approach a target drug molecule
  and improves its iterations by itself.
• This technique can be applied to solve complex
  drug calculations. Desktop computers as well as
  Super-Computers both are employed for Neural
  Networks Drug research.

15
Applications

• 1. Find interesting lead molecules quickly
• 2. Predicting properties and activities of
  untested molecules
• 3. Propose compounds for synthesis
• 4. Validate models of receptor binding sites
• 5. Optimize pharmacokinetic properties of compound

16
Drug Discovery
17
Drug Discovery

• In medicine, biotechnology and pharmacology,
  drug discovery is the process by which drugs are
  discovered
• The process of drug discovery involves the
  identification of candidates, synthesis,
  characterization, screening, and assays for
  therapeutic efficacy.

18
Focused Areas of Research
Metabolic Gastrointestinal
Dermatology
Ophthalmic
Inflammatory/ Immune-related
Neurological/ Pyschotherapeutic
Important DRUG Targets
Oncology/ Cancer
Infectious Disease Microbial/Viral
Cardiovascular/ Blood Disorder
Respiratory
Musculoskeletal
19
Drug Discovery Pathway
Preclinical Studies
Primary Screening Hits
Selection of candidate drug
ADME
Discovery Development
Efficacy
Preformulations Stability Studies
Safety

Toxicology
Leads
20
Drug Discovery Process

• 1. What is an ideal drug?
• (Given by mouth and has a beneficial effect safe
  efficacious in only 50 !)
• 2. What is a promising drug candidate?
• (Most site specific with best combination of
  target affinity, highest bioavailability and
  lowest toxicity)
• 3. How is a lead drug candidate screened for
  ideal
• characteristics?
• (Study of the in vitro ADME/Tox- drug transport ,
  absorption, metabolism, etc)
• Toxicity pharmacokinetics In vivo

21
Drug Discovery Pipeline
Development
Discovery
Exploratory Research
Proteomics
Diagnostics
Expression
Peptide Mass
Profiling
Fingerprinting
Fractionate
Mass
Protein
Spec
Validated
Targets
Pathway Mapping
Lead
Lead
Pre-clinical
Clinical
Identification
Optimization
Protein
Structure
Protein- protein Interactions
Genotyping
Hot
Drug
ADME
Human
H-UHTS
M-HTS
L-MTS
Genome
SNP
Leads
Candidates
PK
Trials
Functional
Genomics
Discovery
Sequencing
Primary
Secondary
Lab
Clinical
Protein
Screening
Screening
Animal Tests
Validation
Gene
Combichem
Localization
Synthesis
Expession
Compound
Genomics
Production
Profiling
Library
Drug Discovery
Natural
Compounds
22
Drug Discovery Process
Compound library generation Combichem

Clinical Trials Clinical monitoring
Assay Development
Discovery Center w/primary secondary
screening Pre-ADME
In vitro in-vivo ADMET
Functional and ADMET screening assays becoming
more important earlier in the screening process.
23
Real drug pipeline
A Absorption Solubility Stability Dissolution Dr
ug Transport
D- Distribution Plasma Protein Binding
assays (PPB)
Targets
Permeability
Drug
24
Overview of Solubility Screening Assay Protocol

• 1. Compound from library is added to buffer and
  mixed in plate.
• 2. Precipitated compound is filtered out.
• 3. Filtrate containing soluble compound is
  analyzed versus standards.

25
Value of Solubility and Permeability for
Absorption
For a particular dose level and permeability
value, the solubility must be above a certain
level to assure oral bioavailability.
26
Cell Membrane Transport Mechanisms
Transcellular Paracellular Active
Transport Active Efflux
27
Membrane structure transport

1. Membranes are two-dimensional solutions of
   oriented lipids and globular proteins that are
   mobile in the plane of the membrane
   fluid-mosaic model
2. Membrane transport is mediated by specific
   integral membrane proteins ion channels,
   porins, transporters (passive), pumps (active)
3. Integral membrane proteins have common structural
   features predominantly transmembrane a helices

28
Ion channels are membrane spanning proteins
29
Opening and closing of channels requires
conformational change
30
Flux of ions through the channels is passive
Extracellular
Intracellular
31
Drug Development
32
Drug Development

• Drug development or preclinical development is
  defined in many pharmaceutical companies as the
  process of taking a new chemical lead through the
  stages necessary to allow it to be tested in
  human clinical trials, although a broader
  definition would encompass the entire process of
  drug discovery and clinical testing of novel drug
  candidates.

33
Drug Discovery Pathway
Preclinical Studies
Primary Screening Hits
Selection of candidate drug
ADME
Discovery Development
Efficacy
Preformulations Stability Studies
Safety

Toxicology
Leads
34
Drug Development Process
35
Reasons for Attrition in Drug Development
36
Barriers of Drug Reaching Target
Stomach pH2
Intestine pH3-8
Blood
Kidneys
Tissues
Cell
Liver
Target
PV
Phase I and II Metabolic stability Metabolite ID
Stability Enzymatic Plasma stability
Permeability Passive Transporters Log D Cell
Exposure
Stability Acidic buffer
Stability Acidic enzymatic buffer
Renal Extraction Log D
Protein binding RBC uptake
Solubility pKa
Permeability Passive P-gp efflux Transportes Log
D
Stability CYP3A metabolic stability
37
Candidate Selection Building Developability
in Preclinical Profiling
Lead (active molecule)
Metabolism
Potency
Potency
Selectivity
Metabolism
Selectivity
LO (optimized molecule)
38
Stability in Physiological Conditions
39
Solubility, Permeability, Chemical and Metabolic
Stability Affects Oral Bioavailability
Portal Vein
Membrane Transfer
Liver Extraction
Solid Drug
Dissolution
Drug in Solution
Absorbed Drug
Systemic Circulation
Solubility
Permeability
Metabolism
40
Physico-chemical profile of NCEs
41
Successful Drug Activity Property
42
Drug Development Process
43
Drug Delivery
44
Drug Delivery

• Drug delivery is the method or process of
  administering a pharmaceutical compound to
  achieve a therapeutic effect in humans or animals
• Drug Delivery technologies are patent protected
  formulation technologies that modifies drug
  release profile, absorption, distribution and
  elimination for the benefit of improving product
  efficacy safety and patient convenience
  compliance

45
Drug Delivery

• Most common methods of delivery include the
  preferred non-invasive peroral (through the
  mouth), topical (skin), transmucosal (nasal,
  buccal/sublingual, vaginal, ocular and rectal)
  and inhalation routes

46
Drug Delivery

• Many medications such as peptide and protein,
  antibody, vaccine and gene based drugs, in
  general may not be delivered using these routes
  because they might be susceptible to enzymatic
  degradation or can not be absorbed into the
  systemic circulation efficiently due to molecular
  size and charge issues to be therapeutically
  effective
• protein and peptide drugs have to be delivered by
  injection.

47
Drug Delivery

• Current efforts in the area of drug delivery
  include the development of targeted delivery in
  which the drug is only active in the target area
  of the body (for example, in cancerous tissues)
  and in which the drug is released over a period
  of time in a controlled manner from a formulate

48
Context Drug Delivery
49
Context Drug Delivery
50
Drug Delivery - Markets
51
Drug Delivery Systems
52
Regulatory Requirements
53
India (Ministry of Health Family Welfare)

• 1. If the drug or its metabolites is related to a
  known carcinogen
• 2. Two species should be used for carcinogenicity
  studies
• 3. At least 3-dose level should be used
• 4. A control group should always be included

54
United States ( FDAs Centre for Drug Evaluation
Research)

• 1. Microbial mutagenicity test
• 2. In vitro mammalian cell mutagenicity test
• 3. Mammalian chromosome test in vitro
• 4. In vitro mammalian cell transformation assay
• 5. Cytogenetic tests in vivo (e.g. bone marrow
  micronucleus test, liver unscheduled DNA
  synthesis UDS test).
• 6. Further in vivo test selection is left to the
  applicant

55
European Community (The Commission of the
European Union)

• 1. An in vitro test for gene mutation in bacteria
• 2. An in vitro test for gene mutation in
  eukaryotic test system (mammalian cells)
• 3. An in vitro test for chromosomal aberration
• 4. An appropriate in vivo assay (usually test for
  chromosomal aberration)

56
Japan ( Ministry of Health Welfare)

• 1. Bacterial reversion test
• 2. In vitro chromosomal aberration test
• 3. In vivo micronuleus test
• Additional tests
• (i) Continuous treatment for 24 and 48 hours with
  and without S9 mix..
• (ii) Pulse treatment for 6 hours (with and
  without S9 mix) followed by sampling at 24 hours.
• (iii) Chromosome preparation for the presence of
  polyploid cells
• (iv) Use of single sex (male) in rodent
  micronucleus test

57
Canada (Health Protection Branch)

• 1. Salmonella/microsome assay.
• 2. Mammalian in vitro chromosome aberration
  assay.
• 3. Mammalian in vivo assay (either metaphase or
  micronucleus test).
• 4. Positive in vivo results may need additional
  in vivo germ cell assay

58
ICH (Regulatory authorities of EU, Japan USA)

• 1. A test for gene mutation in bacteria.
• 2. In vitro chromosomal damage with mammalian
  cells or an in vitro tk assay.
• 3. In vitro test for chromosomal damage using
  rodent haemopoietic cells.
• Additional test
• (i) Measurement of DNA adducts.
• (ii) DNA strand breaks
• (iii) DNA repair or recombination

59
THANK YOU FOR YOUR ATTENTION