drug design:discovery, development and delivery
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19 March 2009 KLE College of Pharmacy, Belgaum 1
Drug Design: Discovery, Development and Delivery
Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D
Associate ProfessorDepartment of Pharmaceutics
KLE UniversityBELGAUM – 590010
E-mail: [email protected] 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 properties2. Receptor-Based modeling3. 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 lipid-water-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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Dermatology
Inflammatory/Immune-related
Oncology/Cancer
RespiratoryCardiovascular/Blood DisorderMusculoskeleta
l
Infectious Disease
Microbial/Viral
Neurological/Pyschotherapeuti
c
Ophthalmic
MetabolicGastrointestinal
Important DRUG Targets
Focused Areas of Research
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Drug Discovery Pathway
Efficacy
ADME
Toxicology
Safety
PreformulationsStability Studies
Leads
Selection ofcandidate drug
Preclinical StudiesPrimary Screening [Hits]
Discovery &Development
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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 ]
Drug Discovery Process
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Drug Discovery Pipeline
ValidatedTargets
Hot Leads
DrugCandidates
ADMEPK
Human Trials
H-UHTS
PrimaryScreening
SecondaryScreening
LeadIdentification
LeadOptimization
Pre-clinical Clinical
Discovery Development
M-HTS
Lab &Animal Tests
L-MTS
Clinical Validation
GenomeSequencing
SNPDiscovery
Genotyping
GeneExpessionProfiling
Exploratory Research
Genomics
Proteomics
Drug Discovery
FractionateProtein
MassSpec
CombichemSynthesis
Natural Compounds
CompoundLibrary
PathwayMapping
Protein
Structu
re
Functional Genomics
Protein- proteinInteractions
ProteinLocalization
ExpressionProfiling
Peptide MassFingerprinting
Production
Diagnostics
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Drug Discovery Process
AssayDevelopment
Discovery Centerw/primary & secondary screening& Pre-ADME
In vitro & in-vivo ADMET
Compound library generationCombichem
Clinical Trials
& Clinical
monitoring
Exploratory Drug Discovery Drug Development
New
Drug
Target Identification
Target Qualification
Validation
Lead Identification
Lead Optimization
Preclinical Development
Clinical Development
NDA
Functional and ADMET screening assays becoming more important earlier in the screening process.
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“Real drug “pipeline”
DrugDrug
Drug
TargetsA – Absorption
Solubility
Stability
Dissolution
Drug Transport
D- Distribution
Plasma Protein Binding assays
(PPB)
“Permeability”
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Cell Membrane Transport MechanismsCell Membrane Transport Mechanisms
TranscellularParacellularActive TransportActive Efflux
OH
OHO
OH
OHOH
N
S
OH
NH2
O
NH
O O
OH
N
N
N
N
O
O
OHH
OH
H
O
H
H
OH H
OH
H
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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 helices
Membrane structure & transport
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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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Extracellular
Intracellular
Flux of ions through the channels is passive
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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
Efficacy
ADME
Toxicology
Safety
PreformulationsStability Studies
Leads
Selection ofcandidate drug
Preclinical StudiesPrimary Screening [Hits]
Discovery &Development
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Drug Development Process
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Reasons for Attrition in Drug Development
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Stomach
pH2Intestine
pH3-8
PV
Blood Kidneys Tissues Cell
Target
Stability
Acidic buffer
Stability
Acidic enzymatic
buffer
Solubility
pKa
Stability
CYP3A metabolic stability
Permeability
Passive
P-gp efflux
Transportes
Log D
Liver
Phase I and II
Metabolic stability
Metabolite ID Protein binding
RBC uptake
Stability
Enzymatic
Plasma
stability
Renal Extraction
Log D
Permeability
Passive
Transporters
Log D
Cell Exposure
Barriers of Drug Reaching Target
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Candidate Selection: Building “Developability” in Preclinical Profiling
Lead (active molecule)
MetabolismSelectivity
Potency
LO (optimized molecule)
Physical properties
Potency
Selectivity
Metabolism
Best leadsPhysical / chemical
propertiesBiopharmaceutics
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Duodenum
Stomach
Ascending colon
Descending colon
Jejunum
Ileum
Small intestine
Transverse colon
Rectum
pH = 1 - 3.5
pH = 5 - 7
pH = 8
Blood = 7.4
Stability in Physiological Conditions
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Solubility, Permeability, Chemical and Metabolic Stability Affects Oral Bioavailability
Solid
DrugDrug in
Solution
Absorbed
Drug
DissolutionMembrane
Transfer
Solubility Permeability
Systemic Circulation
Metabolism
Liver
Extraction
PortalVein
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Physico-chemical profile of NCEs
Permeability
pKa
Stability
PPB Log D
Polymorphism
Lipophilicity
SolubilityIntegrity
Profile
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Successful Drug = Activity + Property
OptimizationActivity
Pharmacology
Property
Pharmaceutical Profiling
In vitro
Solubility
Permeability
BBB & Pgp
Log P & pKa
Metabolism
P450 Inhibition
Stability
Pharmacokinetics
In vivo
Enzyme
Receptor
Cell-based assay
In vitro
Animal Model
In vivo Redesign
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Drug Development Process
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Drug Delivery
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Drug DeliveryDrug 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 DeliveryMany 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 DeliveryCurrent 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
NanoTechnology
DDS
Buccal DDS
Rectal DDS
Vaginal DDS Pulmonary DDS
Nasal DDS
Topical DDS
Parentral DDS
Oral DDS
DeliverySystems
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