19 March 2009KLE College of Pharmacy, Belgaum 1 Drug Design: Discovery, Development and Delivery Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Associate Professor

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


Drug Design


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


Drug Design

1. Rational Drug Design

2. Computer-assisted Drug Design (CADD)

3. Neural network in Drug Design


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



Refining the understanding of pathogenesis



Investigating complex systems increases knowledge return


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



In CoMFA map the colored fields describe how molecular structure can be modified to increase biological activity (CoMFA-Comparative molecular field analysis)



The most commonly used tool to model biological system is molecular dynamics

The model of a receptor refined with molecular dynamics simulations



3D models of membrane receptors can be refined and validated in a realistic lipid-water-salt environment using molecular dynamics simulations



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.



New potent inhibitor for the Human Sirutuin Type 2 enzyme was found using a virtual screening technique


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.


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


Drug Discovery


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.


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


Drug Discovery Pathway

Efficacy

ADME

Toxicology

Safety

Preformulations

Stability Studies

LeadsLeads

Selection ofcandidate drug


Preclinical StudiesPreclinical StudiesPrimary Screening [Hits]

Discovery &Development


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


Drug Discovery Pipeline

Validated

Targets

Hot

Leads

Drug

Candidates

ADME

PK

Human

TrialsH-UHTS

PrimaryScreening

SecondaryScreening

Lead

Identification

Lead

OptimizationPre-clinical Clinical

Discovery Development

M-HTS

Lab &Animal Tests

L-MTS

Clinical Validation

Genome

Sequencing

SNPDiscovery

Genotyping

Gene

ExpessionProfiling

Exploratory Research

Genomics

Proteomics

Drug Discovery

FractionateProtein

MassSpec

CombichemSynthesis

Natural Compounds

CompoundLibrary

PathwayMapping

Prote

in

Structu

re

Functional Genomics

Protein- proteinInteractions

ProteinLocalization

ExpressionProfiling

Peptide MassFingerprinting

Production

Diagnostics


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.


“Real drug “pipeline”

Drug

Drug

Drug

Targets

A – Absorption

Solubility

Stability

Dissolution

Drug Transport

D- Distribution

Plasma Protein Binding assays

(PPB)

“Permeability”


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

O

H

H

O

H

H

OH H

OH

H


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


Ion channels are membrane spanning proteins


Opening and closing of channels requires conformational change


Extracellular

Intracellular

Flux of ions through the channels is passive


Drug Development


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.


Drug Discovery Pathway

Efficacy

ADME

Toxicology

Safety

Preformulations

Stability Studies

LeadsLeads



Preclinical StudiesPreclinical StudiesPrimary Screening [Hits]

Discovery &Development


Drug Development Process


Reasons for Attrition in Drug Development


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 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


Candidate Selection: Building “Developability” in Preclinical Profiling

Lead (active molecule)

MetabolismSelectivity

Potency

LO

(optimized molecule)

Physical properties

Potency

Selectivity

Metabolism

Best leadsPhysical / chemical

propertiesBiopharmaceutics


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


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

PortalVein


Physico-chemical profile of NCEs

Permeability

pKa

Stability

PPB Log D

Polymorphism

Lipophilicity

Solubility

Integrity

Profile


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


Drug Development Process


Drug Delivery


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


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


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.


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


Context – Drug Delivery


Context – Drug Delivery


Drug Delivery - Markets


Drug Delivery Systems

NanoTechnology

DDS

Buccal DDS

Rectal DDS

Vaginal DDSPulmonary

DDS

Nasal DDS

Topical DDS

Parentral DDS

Oral DDS

DeliverySystems


Documents

19 March 2009KLE College of Pharmacy, Belgaum 1 Drug Design: Discovery, Development and Delivery Dr. Basavaraj K. Nanjwade M.Pharm., Ph.D Associate Professor