Transcript Drug Design: Discovery, Development and Delivery Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Associate Professor Department of Pharmaceutics KLE University BELGAUM – 590010 E-mail: [email protected] Cell No: 0091 9448716277 19

Drug Design: Discovery, Development
and Delivery
Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D
Associate Professor
Department of Pharmaceutics
KLE University
BELGAUM – 590010
E-mail: [email protected]
Cell No: 0091 9448716277
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Drug Design
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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
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Drug Design
1. Rational Drug Design
2. Computer-assisted Drug Design (CADD)
3. Neural network in Drug Design
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Rational Drug Design
The industry now has the research tools to pursue
rational Drug Design successfully, but a new hurdle is
being raised:finding 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
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Rational Drug Design
Refining the understanding of pathogenesis
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Rational Drug Design
Investigating complex systems increases knowledge return
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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
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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)
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Computer-assisted Drug Design (CADD)
 The most commonly used tool to model
biological system is molecular dynamics
 The model of a receptor refined with molecular
dynamics simulations
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Computer-assisted Drug Design (CADD)
3D models of membrane receptors can be refined and validated in a realistic lipidwater-salt environment using molecular dynamics simulations
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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.
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Computer-assisted Drug Design (CADD)
New potent inhibitor for the Human Sirutuin Type 2 enzyme was found
using a virtual screening technique
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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.
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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
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Drug Discovery
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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.
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Focused Areas of Research
Metabolic
Gastrointestinal
Dermatology
Ophthalmic
Neurological/
Pyschotherapeutic
Inflammatory/
Immune-related
Important DRUG
Targets
Infectious Disease
Microbial/Viral
Oncology/
Cancer
Musculoskeleta
l
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Cardiovascular/
Blood Disorder
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Respiratory
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Drug Discovery Pathway
Preclinical Studies
Primary Screening
[Hits]
Selection of
candidate drug
ADME
Efficacy
Discovery
&
Preformulations
Development
Stability Studies
Safety
Toxicology
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Leads
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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 ]
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Drug Discovery Pipeline
Exploratory Research
Development
Discovery
Proteomics
Diagnostics
Peptide Mass
Fingerprinting
Expression
Profiling
Fractionate Mass
Protein
Spec
Validated
Targets
Lead
Identification
Lead
Optimization
Pre-clinical
Clinical
Genotyping
Genome
Sequencing
SNP
Discovery
Genomics
H-UHTS
Functional Genomics
Gene
Expession
Profiling
Combichem
Synthesis
Primary
Screening
Compound
Library
Natural
Compounds
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Hot
Leads
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M-HTS
Drug
ADME
L-MTS
Candidates
PK
Secondary
Screening
Human
Trials
Lab &
Clinical
Animal Tests Validation
Production
Drug Discovery
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Drug Discovery Process
Exploratory
Drug Discovery
Compound library
generation
Combichem
Drug Development
Target
Clinical
Lead
Lead
Preclinical
Target
Qualification
Identification Validation Identification Optimization Development Development
New
NDA
Drug
Assay
Development
Discovery Center
w/primary &
secondary screening
& Pre-ADME
In vitro
& in-vivo
ADMET
Clinical
Trials
&
Clinical
monitoring
Functional and ADMET screening assays
becoming more important earlier in the
screening process.
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“Real drug “pipeline”
A–
Absorption
DDistribution
Solubility
Stability
Dissolution
Drug
Transport
Drug
Targets
Plasma
Protein
Binding
assays “Permeability”
(PPB)
Drug
Drug
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Cell Membrane Transport Mechanisms
O H
Transcellular
Paracellular
Active Transport
Active Efflux
HO
O
H
HO
O
OH
N
N
OH
H
O
OH
O
NH2
H
S
H
N
N
H
H
O
H
O
OH
O
HO
N
N
H
O
H
O
O
H
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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
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Ion channels are membrane spanning proteins
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Opening and closing of channels requires
conformational change
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Flux of ions through the channels is passive
Extracellular
Intracellular
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Drug Development
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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.
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Drug Discovery Pathway
Preclinical Studies
Primary Screening
[Hits]
Selection of
candidate drug
ADME
Efficacy
Discovery
&
Preformulations
Development
Stability Studies
Safety
Toxicology
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Leads
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Drug Development Process
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Reasons for Attrition in Drug
Development
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Barriers of Drug Reaching Target
Stomach
pH2
Intestine
pH3-8
Blood
Liver
Kidneys
Tissues
Cell
Target
PV
Stability
Stability
Phase I and II
Acidic
buffer
Acidic
enzymatic
Metabolic
stability
Stability
Metabolite ID Protein
binding
buffer
Enzymatic
Passive
Plasma
Log D
Transporters
stability
RBC
uptake
Solubility
Permeability
Renal
Extraction
Log D
Cell Exposure
pKa
Permeability
Stability
Passive
CYP3A
metabolic
stability
P-gp efflux
Transportes
Log D
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Candidate Selection: Building “Developability” in
Preclinical Profiling
Lead
(active molecule)
Physical properties
Potency
Metabolism
Potency
Metabolism
Selectivity
Selectivity
Best leads
LO
(optimized molecule)
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Physical / chemical
properties
Biopharmaceutics
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Stability in Physiological Conditions
Blood = 7.4
Stomach
pH = 1 - 3.5
Transverse
colon
Duodenum
pH = 5 - 7
Small intestine
Jejunum
Ascending colon
Ileum
Descending colon
pH = 8
Rectum
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Solubility, Permeability, Chemical and Metabolic
Stability Affects Oral Bioavailability
Solid Dissolution Drug in
Drug
Solution
Solubility
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Membrane
Portal
Vein
Liver
Transfer
Absorbed
Extraction
Drug
Permeability
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Systemic
Circulation
Metabolism
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Physico-chemical profile of NCEs
Integrity
Permeability
Solubility
Lipophilicity
pKa
Profile
Stability
Polymorphism
PPB
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Log D
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Successful Drug = Activity + Property
In vitro
Solubility
Permeability
In vitro
BBB & Pgp
Log P & pKa
Metabolism
Enzyme
Pharmacology
Pharmaceutical Profiling
Receptor
P450 Inhibition
Stability
Cell-based assay
Activity
Optimization
Animal Model
In vivo
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Property
Pharmacokinetics
Redesign
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In vivo
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Drug Development Process
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Drug Delivery
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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
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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
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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.
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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
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Context – Drug Delivery
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Context – Drug Delivery
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Drug Delivery - Markets
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Drug Delivery Systems
Oral DDS
Nano
Technology
DDS
Parentral
DDS
Topical DDS
Buccal DDS
Delivery
Systems
Rectal DDS
Nasal DDS
Vaginal DDS
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Pulmonary
DDS
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