Drug discovery

DRUG DISCOVERY&

DEVELOPMENTBY DR. SABA AHMED

M PHIL PHARMACOLOGY UOS

INTRODUCTION

• In the past most drugs have been discovered either by identifying the

active ingredient from traditional remedies or by serendipitous

discovery.

• But now we know diseases are controlled at molecular and

physiological level.

• Also shape of an molecule at atomic level is well understood.

HISTORY OF DRUG DISCOVERY Pre 1919• Herbal Drugs• Serendiptious

discoveries

1920s, 30s• Vitamins• Vaccines

1940s• Antibiotic Era• R&D Boost due to WW2

1950s• New technology,• Discovery of DNA

1960s• Breakthrough in

Etiology

1970s• Rise of Biotechnology• Use of IT

1980s• Commercialization of

Drug Discovery• Combinatorial

Chemistry

1990s• Robotics• Automation

TOP COMPANIES BY R&D EXPENSESr. No. Company R & D spend($bn)

1 Novartis 7.92 Merck & Co 8.13 Roche 7.84 GlaxoSmithKline 5.75 Sanofi 5.86 Pfizer 9.17 Johnson & Johnson 4.58 Eli Lilly 4.79 AstraZeneca 4.2

10 Takeda 3.411 Bayer 2.312 Bristol-Myers Squibb 3.313 Boehringer Ingelheim 3.114 Amgen 2.815 Novo Nordisk 1.7

THE PROCESSTHE PROCESS

In broader sense drug discovery and development can be defined • “A process that starts with the identification of disease and therapeutic

target of interest and include methodology, assay development ,lead identification and characterization in vitro ,formulation and animal pharmacological studies ,pharmacokinetics and safety studies in animals and clinical studies in the human .”Different stages include

Basic research Feasibility studies Programme Non-Clinical development Clinical Development

10,000COMPOUNDS

250COMPOUNDS 5 COMPOUNDS

1 FDA APPROVED

DRUG

~6.5 YEARS ~7 YEARS ~1.5 YEARS

DRUG DISCOVERY

PRECLINICAL

CLINICAL TRIALS FDAREVIEW

Drug Discovery & Development-Timeline

Target Selection

• Cellular and Genetic Targets

• Genomics

• Proteomics

• Bioinformatics

Lead Discovery

• Synthesis and Isolation

• Combinatorial Chemistry

• Assay development

• High-Throughput Screening

Medicinal Chemistry

• Library Development

• SAR Studies

• In Silico Screening

• Chemical Synthesis

In Vitro Studies

• Drug Affinity and Selectivity

• Cell Disease Models

• MOA

• Lead Candidate Refinement

Preclinical studies

• Animal models of Disease States

• Behavioural Studies

• Functional Imaging

• Ex-Vivo Studies

Clinical Trials and

Therapeutics

DRUG DISCOVERY

DRUG DISCOVERY

• It is phase during which the candidates or target of interest are selected on the

basis of their pharmacological bases

• Drugs Discovery methods:

– Random Screening

– Molecular Designing

– Drug Metabolites

– Serendipity

Target Selection Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Cellular & Genetic Targets

Genomics

Proteomics

Bioinformatics

TARGET SELECTION

• Target selection in drug discovery is defined as the decision to focus on

finding an agent with a particular biological action that is anticipated to have

therapeutic utility

• Target identification: to identify molecular targets that are involved in

disease progression.

• Target validation: to prove that manipulating the molecular target can

provide therapeutic benefit for patients.


Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials


Genomics

Proteomics

Bioinformatics

TARGET SELECTIONBiochemical Classes of Drug Targets

G-protein coupled receptors - 45%

enzymes - 28%

hormones and factors - 11%

ion channels - 5%

nuclear receptors - 2%

Techniques for Target Identification


Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials


Genomics

Proteomics

Bioinformatics


•Involves the identification of the function of a potential therapeutic drug target and its role in the disease process

•Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease.


Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials


Genomics

Proteomics

Bioinformatics

Genomics•The study of genes and their function. Genomics aims to understand the structure of the genome, including the mapping genes and sequencing the DNA.

•Human Genome consists of a sequence of around 3 billion nucleotides (the A C G T bases) which in turn probably encode 35,000 – 50,000 genes.


Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials


Genomics

Proteomics

Bioinformatics

Proteomics•It is the study of the proteome, the complete set of proteins produced by a species, using the technologies of large – scale protein separation and identification.

•It is also at the protein level that disease processes become manifest, and at which most (91%) drugs act. •Therefore, the analysis of proteins (including protein-protein, protein-nucleic acid, and protein ligand interactions) will be utmost importance to target discovery.


Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials


Genomics

Proteomics

Bioinformatics

Continued….•Proteomics is the systematic high-throughput separation and characterization of proteins within biological systems.

•Target identification with proteomics is performed by comparing the protein expression levels in normal and diseased tissues.


Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials


Genomics

Proteomics

Bioinformatics

BioinformaticsBioinformatics is a branch of molecular biology that involves extensive

analysis of biological data using computers, for the purpose of enhancing biological research.

It plays a key role in various stages of the drug discovery process including

target identification

computer screening of chemical compounds and


Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials


Genomics

Proteomics

Bioinformatics

Continued…•Bioinformatics methods are used to transform the raw sequence into meaningful information (eg. genes and their encoded proteins) and to compare whole genomes (disease vs. not).

•Can compare the entire genome of pathogenic and non-pathogenic strains of a microbe and identify genes/proteins associated with pathogenism •Using gene expression micro arrays and gene chip technologies, a single device can be used to evaluate and compare the expression of up to 20000 genes of healthy and diseased individuals at once


Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Synthesis and Isolation

Combinatorial Chemistry

Assay Development

High Throughput Screening

LEAD DISCOVERY• A lead compound is an organic molecule that act as

a prototype drug around which further optimization is centered and focused”

• Identification of small molecule modulators of protein function

• The process of transforming these into high-content lead series.


Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials



Assay Development


Synthesis and Isolation• Separation of mixture

• Separation of impurities

• In vitro chemical synthesis

• Biosynthetic intermediate

Approaches For Lead DiscoverySerendipity:

• It is to follow when chance is very less. It has been the historically the most successful way

of discovering the drugs. E.g discovery of lavemisol,Vaproic acid.

Endogenous Source:

• Human disease arises from disturbance of the normal biochemical processes. A logical

therapeutic approach is the administration of one or more of these naturally occurring

endogenous molecules or their analougues.The most important approach under this source

is Peptidomimetic Chemistry using non-peptides to mimic endogenous peptide activity.Target Selection Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Continued…Exogenous Source: (Ethanobotany or Ethanopharmacology)

• The molecules which are endogenous to the other life form such as plants and animals but do

not occur naturally within human body ,such molecules are classed as exogenous molecule for

prospective of drug designing for human beingsRational Drug Design• Approximately 2000 small molecules that theoretically exist in our world out of which 1052 are drug like molecules and many of which are purely synthetic and cannot occur

naturally. Thus there is an opportunity to explore the none naturally occurring synthetic compounds as potential source of lead compound


Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials



Assay Development


Continued…Combinatorial Chemistry

Rapid synthesis of or computer simulation of large no. of different but structurally

related molecules

• Search new leads

• Optimization of target affinity & selectivity.

• ADME properties

• Reduce toxicity and eliminate side effects


Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials



Assay Development


Continued…High throughput screening

• It refers to the process by which pharmaceutical companies are able to obtain

initial screening data up to 1 million compounds testing against as many as 50

different biological targets/years. This expansion of data collection by several

orders of magnitude is primarily due to advancement in Robotics,

combinatorial chemistry and instrumentation.

• Screening of drug target against selection of chemicals.

• Identification of highly target specific compounds.

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Assay Development• Used for measuring the activity of a drug.

• Discriminate between compounds.

• Evaluate:

• Expressed protein targets.

• Enzyme/ substrate interactions.



Assay Development


Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Library Developmen

t

SAR StudiesIn Silico

ScreeningChemical Synthesis

MEDICINAL CHEMISTRY• It’s a discipline at the intersection of synthetic organic chemistry and

pharmacology.

• Focuses on small organic molecules (and not on biologics and

inorganic compounds)

• Used in

• Drug discovery (hits)

• Lead optimization (hit to lead)

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

In Vivo Studies

Clinical Trials

Library Developme

nt



Library Development

• Collection of stored chemicals along with associated

database.

• Assists in High Throughput Screening

• Helps in screening of drug target (hit)

• Based on organic chemistry

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

In Vivo Studies

Clinical Trials

Library Developme

nt



SAR Studies• Helps identify pharmacophore

• The pharmacophore is the precise section of the molecule that

is responsible for biological activity

• Enables to prepare more active compound

• Allow elimination of excessive functionality

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Library Developme

nt



In silico screening• Computer simulated screening of chemicals

• Helps in finding structures that are most likely to

bind to drug target.

• Economic than HTS

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Library Developme

nt



Chemical Synthesis• Involve production of lead compound in suitable quantity

and quality to allow large scale animal and eventual,

extensive human clinical trials

• Optimization of chemical route for bulk industrial

production.

• Suitable drug formulation

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Drug Affinity

and Selectivi

ty

Cell Disease Models

MOA

Lead Candidate Refinement

In Vitro Studies• (In glass) studies using component of organism i.e. test tube

experiments• Examples-

• Cells derived from multicellular organisms• Subcellular components (Ribosomes, mitochondria)• Cellular/ subcellular extracts (wheat germ, reticulocyte

extract)• Purified molecules (DNA,RNA)

THEORATICLE AND PRACTICLE ASPECT OF DRUG

DEVELOPMENT

PRECLINICAL STUDIES• The aim of this stage is to satisfy all the requirements that have to be met before a

new compound is deemed ready to be tested for the first time in humans. The work

falls into four categories

• Pharmacological testing

• Preliminary Toxicological testing

• Pharmacokinetics studies i.e ADME studies

• Chemical and pharmaceutical assessment to assess the feasibility of large scale

synthesis and purification.

Animal models

of Disease States

Behavioural Studies

Functional ImagingEx-Vivo Studies

Target Selection

Lead Discover

y

Medicinal Chemistr

yIn Vitro Studies

Preclinical studies

Clinical Trials

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Animal models

of Disease States

Behavioural Studies


PRECLINICAL STUDIES

• Its experimentation using a whole, living organism.

• Gives information about,

• Metabolic profile

• Toxicology

• Drug interaction

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Animal models

of Disease States

Behavioural Studies


Animal models of disease states

• Test conditions involving induced disease or injury similar to

human conditions.

• Must be equivalent in mechanism of cause.

• Can predict human toxicity in 71% of the cases.

• Eg. SCID mice-HIV

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Animal models

of Disease States

Behavioural Studies


Behavioural Studies• Tools to investigate behavioural results of drugs.

• Used to observe depression and mental disorders..

• Example:

• Despair based- Forced swimming/ Tail suspension

• Reward based

• Anxiety Based

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical Studies

Clinical Trials

Animal models

of Disease States

Behavioural Studies


Functional Imaging• Method of detecting or measuring changes in metabolism,

blood flow, regional chemical composition, and absorption.

• Tracers are used

• MRI

• CT-Scan

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Animal models

of Disease States

Behavioural Studies


Ex-Vivo Studies• Experimentation on tissue in an artificial environment outside the

organism with the minimum alteration of natural conditions.

• Counters ethical issues.

• Examples:

• Measurement of tissue properties

• Realistic models for surgery

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Phase-I

Phase-II

Phase-IIIPhase-IV

CLINICAL TRIALS

• Set of procedures in medical research and drug

development to study the safety and efficacy of new

drug.

• Essential to get marketing approval from regulatory

authorities.

• May require upto 7 years.

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Phase-I

Phase-II

Phase-IIIPhase-IV

Phase I:• Clinical Pharmacologic Evaluation

• First stage of testing in human subjects.

• 20-50 Healthy Volunteers

• Concerned With:

– Human Toxicity.

– Tolerated Dosage Range

– Pharma-cology/dynamics

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Phase-I

Phase-II

Phase-IIIPhase-IV

Phase II:• Controlled Clinical Evaluation.

• 50-300 Patients

• Controlled Single Blind Technique

• Concerned With:

– Safety

– Efficacy

– Drug Toxicity&Drug Interaction

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Phase-I

Phase-II

Phase-IIIPhase-IV

Phase III:

• Extended Clinical Trials.

• Most expensive & time consuming.

• 250-1000 Patients.

• Controlled Double Blind Technique.

• Concerned With:

– Safety, Efficacy

– Comparison with other Drugs

– Package Insert

Target Selection

Lead Discovery

Medicinal Chemistry

In Vitro Studies

Preclinical studies

Clinical Trials

Phase-I

Phase-II

Phase-IIIPhase-IV

Phase IV:

• Post Marketing Surveillance.

• Designed to detect any rare or long-term adverse effects.

• Adverse Drug Reaction Monitoring

RECENT RESEARCHES

ABSTRACT 1• A review article highlight the use of genomics and proteomics in pharmaceutical drug discovery and development

stating that One of the most pressing issues facing the pharmaceutical industry is the tremendous dropout rate of lead

drug candidates. Genomics and proteomics are today well established in drug discovery and development, in

combination with combinatorial chemistry and high-throughput screening, are helping to bring forward a matchless

number of potential lead compounds. Over the last two decades, several new genomic technologies have been

developed in hopes of addressing the issues of target identification and lead candidate optimization. Proteomics is a

technology platform that is gaining widespread use in drug discovery and drug development programs. Defined as

the protein complement of the genome, the proteome is a varied and dynamic repertoire of molecules that in many

ways dictates the functional form that is taken by the genome. We focus in this article on recent progress and

innovations utilizing “omics” technologies to identify and validate drug targets, discover disease biomarkers, and

design more effective drugs.( SHARMA NEHA and HARIKUMAR S.L,2013)4

ABSTRACT 2• A study carried out by Abdul Wadood et al(2014) on the in silico technique illustrates that Hepatitis C virus (HCV) infection

is an alarming and growing threat to public health. The present treatment gives limited efficacy and is poorly tolerated,

recommending the urgent medical demand for novel therapeutics. NS3/4A protease is a significant emerging target for the

treatment of HCV infection. This work reports the complex-based pharmacophore modeling to find out the important

pharmacophoric features essential for the inhibition of both protease and helicase activity of NS3/4A protein of HCV. A seven

featured pharmacophore model of HCV NS3/4A protease was developed from the crystal structure of NS3/4A protease in

complex with a macrocyclic inhibitor interacting with both protease and helicase sites residues via MOE pharmacophore

constructing tool. It consists of four hydrogen bond acceptors (Acc), one hydrophobic (Hyd), one for lone pair or active

hydrogen (Atom L) and a heavy atom feature (Atom Q). The generated pharmacophore model was validated by a test

database of seventy known inhibitors containing 55 active and 15 inactive/least active compounds. The validated

pharmacophore model was used to virtually screen the ChemBridge database. As a result of screening 1009 hits were

retrieved and were subjected to filtering by Lipinski’s rule of five on the basis of which 786 hits were selected for further

assessment using molecular docking studies. Finally, 15 hits of different scaffolds having interactions with important active

site residues were predicted as lead candidates. These candidates having unique scaffolds have a strong likelihood to act as

further starting points in the development of novel and potent NS3/4A protease inhibitors.( Abdul Wadood,et al,2014)6

)

RECENTLY APPROVED DRUGS BY FDA(2014

Generic

Therapeutic Use

Testosterone undecanoate Treatment of hypogonadism

Dapagliflozin Type II diabetes

Droxidopa Neurogenic orthostatic hypotension

Ibrutinib Chronic lymphocytic leukemia

Tasimelteon Non-24-hour sleep-wake disorder

Health & Medicine

Drug discovery