Drug Design:Discovery, Development and Delivery

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:
DrugDesign
,
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 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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Dermatolog
y
Inflammatory/
Immune-related
Oncology/
Cancer
Respirator
y
Cardiovascular/
Blood Disorder
Musculoskeleta
l
Infectious
Disease
Microbial/Viral
Neurological/
Pyschotherapeuti
c
Ophthalmic
Metabolic
Gastrointestinal
Important DRUG
Targets
Focused Areas of Research

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Drug Discovery Pathway
Efficacy
ADME
Toxicology
Safety
Preformulations
Stability Studies
Leads

Selection of
candidate drug
Preclinical Studies
Primary 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
Validated
Targets
Hot
Leads
Drug
Candidates
ADME
PK
Human
Trials
H-UHTS
Primary
Screening
Secondary
Screening
Lead
Identification
Lead
Optimization
Pre-clinicalClinical
Discovery Development
M-HTS
Lab &
Animal Tests
L-MTS
Clinical
Validation
Genome
Sequencing
SNP
Discovery
Genotyping
Gene
Expession
Profiling
Exploratory Research
Genomics
Proteomics
Drug Discovery
Fractionate
Protein
Mass
Spec
Combichem
Synthesis
Natural
Compounds
Compound
Library
Pathway
Mapping
P rot ein
S t ru ct ure
Functional Genomics
Protein-
protein
Interactions
Protein
Localization
Expression
Profiling
Peptide Mass
Fingerprinting
Production
Diagnostics

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Drug Discovery Process
Assay
Development
Discovery Center
w/primary &
secondary screening
& Pre-ADME
In vitro
& in-vivo
ADMET
Compound library
generation
Combichem
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”
Drug
Drug
Drug
Targets
A –
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
Transcellular
Paracellular
Active Transport
Active Efflux
OH
OH
O
OH
OH
OH
N
S
OH
NH
2
O
N
H
O O
OH
N
N
N
N
O
O
O
HH
O
H
H
O
H
H
O
H H
O
H
H

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

Selection of
candidate drug
Preclinical Studies
Primary 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
pH2
Intestine
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 IDProtein
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)
Metabolism
Selectivity
Potency
LO
(optimized molecule)
Physical properties
Potency
Selectivity
Metabolism
Best leads
Physical / chemical
properties
Biopharmaceutics

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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
Drug
Drug in
Solution
Absorbed
Drug
Dissolution
Membrane
Transfer
Solubility Permeability
Systemic
Circulation
Metabolism
Liver
Extraction
Portal
Vein

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Physico-chemical profile of NCEs
Permeability
pKa
Stability
PPB Log D
Polymorphism
Lipophilicity
Solubility
Integrity
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 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
Nano
Technology
DDS
Buccal DDS
Rectal DDS
Vaginal DDS
Pulmonary
DDS
Nasal DDS
Topical DDS
Parentral
DDS
Oral DDS
Delivery
Systems

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