Presented by- Nitin

October-2013

Trends in pharmacological sciences

Contents

Building better drugs: developing and regulating engineered therapeutic proteins

Therapeutic proteins Although a reliable count of functionally distinct proteins in humans is lacking,

estimates suggest that the number runs to at least several tens of thousands

Abnormality in one or more of these proteins leads to disease conditionTherapeutic proteins represented 17% of new drugs approved by the USA Food

and Drug Administration (FDA) in 2005 but increased to 32% by 2011 Factors VIII and IX as replacement therapy for hemophilia has significantly

extended the life expectancy of patients

WithdrawalsDue to safety issuesVatreptacog alpha, BAY86-6150 bioengineered recombinant factor VIIa

Hypersensitivity reactionsPeginesatide, a novel functional analog of erythropoietin

Engineered proteins: therapeutics by designNeed- very short serum half-life and poor bioavailability heterologous expression systems such as E. coli or yeast lack post-translational modifications

Technologies: Fusion proteins- unstructured recombinant polypeptides called XTEN have been

successfully used to generate fusion proteins with improved pharmacokinetic properties Also PEGylated proteins

Alteration of sequenceDeletions, insertions, and point mutations in a wild type sequence are performedeg. deletion of the B-domain of Factor VIII results in higher secretion of the protein into

the media as compared with the full-length form of Factor VIII

Codon optimization Codon optimization is a technique to maximize the protein expression

Reports increase up to 30-foldCodon optimization softwares-GENEMAKER, General Codon Usage Analysis (GCUA) -a

program Gene composer, Gene designer, JCat , Optimizer etc

Concluding remarksThere has been unprecedented progress, during the past decade, in

the development of platform technologies that further being improved

The rapid progress of many different scientific disciplines holds promise for more predictable criteria for the licensure of these products

And less burdensome regulatory requirements

Pharmacology in China: Overview

1. Formation(1923–1949)Part of Chinese civilization for more than 5000 years, Contemporary

pharmacology in China began around 1930Ephedra - Dr K.K. Chen, paved the way for subsequent exploration in

sympathomimetics.The Chinese Society of Physiology in 1926 2. Growth(1949–1985)Experienced a steady growth since 1949 Major discoveries in this

period include sodium dimer-captosuccinnate, antitumor agents such as camptothecins, hydroxycamptothecins

Treatment of acute promyelocytic leukemia with all-trans retinoic acid was another original discovery made in China

Then came period of ‘ cultural revolution’Chinese Pharmacological Society was established in 1979 and started

to publish a journal in English – Acta Pharmacologica Sinica in 1980.

The society finally joined the International Union of Pharmacology (IUPHAR) in 1985, signaling China’s entry onto the international stage of pharmacology

Expansion (1986–present)Since China joined the World Trade Organization (WTO) in 2001, funding

for scientific research has risen steadily. National Centre for Drug Screening (NCDS) along with a number of other

Recently via the foundation of the Chinese National Compound Library (CNCL) HAVE approx.1.3 million sample collections

Outlook Although pharmacological studies on TCM will continue to be a focal point,

strong emphases will be directed towards basic and original research ‘Lead Project’ on personalized medicine at the Chinese Academy of

Sciences

Computational methods for drug design and discovery: focus on ChinaDrug discovery in ChinaTaking the structure-based drug design (SBDD) as an example, the publication of scientific papers from China during 2006 to 2010 ranked fifth (citation ranking is seventh)Among Asian countries, China ranked the top in both the number of publications and citations

Computational strategies and techniques in drug designPharmacophore modellingMeasures to what extent a query molecule possesses the spatial arrangement of features essential for protein–ligand interaction, requires less time to screen a ligand than dockingReverse dockingIdentifying targets is the first key step, One of the computational approaches demonstrated to be efficient and cost effective in target identificationThe identified protein ‘hit’ can then serve as a potential candidate

Drug repositioningTo boost the productivity of the current drug design process “new uses for

an existing drug”.Besides classical target- and ligand-based computational methods, in

recent years, many drug repositioning approaches based on systems biology have been developed. For ex.- network-based inference (NBI) method which used the topology similarity of the ligand–target network to prioritize new targets for a given drug, or vice versa.

There are some databases that focus on the biological actions of drugs, for example, DrugBank, TTD , SuperTarget and MATADOR , STITCH (search tool for interactions of chemicals)

Protein–ligand interactionMolecular docking plays a central role in predicting protein–ligand

interactions, which has been extensively used for drug hit discovery and lead optimization

Virtual screening and lead optimizationHit identification also VS.A useful VS tool named SHAFTS (SHApe FeaTure Similari- ty) , which is a

hybrid approach comparing both molecular shape and pharmacophore features

1. Pharmacophore-based VS is an established in silico tool that has resulted in the identification of many active compounds in drug discovery programs.

2. . Shape-based VS is another useful tool for searching for novel lead compounds

3. Commercial chemical libraries for high-throughput screening (HTS) are primary sources for hit identification

In silico prediction of ADME/T propertiesThese properties to the failure rates of drug discovery and the resultant

mounting cost of bringing a new drug to the marketWeb-based SOM prediction service, provides medicinal chemists a visual and

easy-to-use interface for addressing some metabolism-related problems.

Successful applications of CDDD Cases of drug target identificationA natural product isolated from ‘Ceratostigma willmottianum’ was found

effective in inhibiting the bacterium- H.PyloriFinding using Tar- FisDock includes revealing the mechanism of

gingerol (in control n management of cancer)Another case study of in silico target prediction include fibroblast growth

factor receptors (FGFRs), as targets for the treatment of various human cancers.

Qian and colleagues used the reverse pharmacophore mapping approach PharmMapper to identify target candidates for an active compound that they previously synthesized and showed great in vitro antiproliferative effects

Cases of hit discoveryMolecular docking is one of the most widely employedNew Delhi metallo-b-lactamase-1 (NDM-1) has recently attracted

extensive attention for its rapid dissemination and resistance to

almost all known b-lactam antibiotics, Shen et al provided useful clues for the rational design of effective NDM-1 inhibitors

Another distinguished contribution made by Chinese researchers is the identification of a new indication for an old drug cinanserin, a well-characterized serotonin antagonist

Concluding remarksCDDD is a multidisciplinary technology SPEEDS UP DD The philosophy embodied in CDDD is shifting from ‘one gene, one

drug, and one disease’ to ‘multicomponent therapeutics, network targets

Regulation of the Hippo pathway and implications for anticancer drug development

Hippo tumor suppressor pathway also known as the Salvador/Warts/Hippo (SWH) pathway

The Hippo– YAP/TAZ pathway was linked to diverse G-protein coupled receptor (GPCR) ligands and receptor signalling

Role in organ size regulation and tumorigenesis Composition of hippo pathway In mammals, the core components of the Hippo pathway

consist of serine/threonine kinases MST1/2, Lats1/2 and their adaptor proteins Sav1 and Mob MOBKL1A and MOBKL1B

Control by the Hippo pathway implicated in diverse cellular and tissue properties which includes-

apicobasal polarity,

• Cell- cell adhesion1• Contact inhibition2• Planer cell polarity3• Mechanotransducti

on4• Various diffusible

signals5

Dysregulation: caused by gene mutation or aberrant expression, promotes cell proliferation and tumorigenesis

Recent advances related with hippo pathway 1. Recent reports show that Ga12/13-, Gaq/11-, Gai/o-coupled

GPCRs activate YAP/TAZ and promote nuclear translocation 2. Gas-coupled GPCRs suppress YAP/TAZ activity 3. Also, dobutamine- a Ga-coupled b-adrenergic agonist, inhibits

YAP-dependent gene transcription 4. Epinephrine and glucagon also inhibit YAP/TAZ activity by

activation of Gas–cAMP–protein kinase A (PKA)–Lats1/2 5. Growth factor signalling:

TGF-bIGF

EGF Interact with several effectors of those pathways such as b-catenin

and Smad proteins WHERE AS, impact on human cancer in which YAP/TAZ are highly

expressed

Structural and energetic analysis of drug inhibition of the influenza A M2 proton channel

Type A influenza virus matrix protein 2 (A M2) highly selective proton channel in the viral envelope Role in viral infection and replication- a target of anti-

influenza drugs Drugs acting through these channelsAmantadineRimantadineProblem- these drugs have met with resistance! M2 channel

Homotetramer comprising four 97- residue transmembrane (TM) peptides The TM domain is composed of four parallel a helices

Drug design targeting drug-resistant mutant M2 channels

Involves following approaches:1. Pharmacophores of adamantane-based drugs

includes one large hydrophobic adamantane group and a polar group, mimicking the structures of amantadine and rimantadine

2. Designing drugs with novel scaffolds M2 channel is structurally flexible, can accommodate hydrophobic groups with different shapes and sizes Using different types of hydrophobic groups

3. Drug design targeting the S31N mutant S31N mutation introduces large polar Asn31 side chains and abolishes the hydrophobic interactionsAccomplished by Ammonium group placed with variations

From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists

5-HT system Have established impact on drug therapy arena of CNS acting drugs In 2000 top five selling central nervous system (CNS) drugs had a

modulatory effect on 5-HT function as a recognized part of their mechanism of action

In obesity control of ingestive behavior, modulation of behavioral effects Lorcaserin (Lorqess) – was approved by the FDA in 2012 for the

treatment of obesity alter various behaviors and underlying neurobiological systems

relevant to drug abuse and addiction likely act directly on paraventricular nucleus to alter metabolic aspects of

feeding

Characteristics of the 5-HT2C receptorOnly known G protein-coupled receptor (GPCR) that

undergoes RNA editingDiffering behavioral phenotypes have also been described

in transgenic mice expressing specific isoforms of 5-HT2C

The ability of fenfluramine and sibutramine to reduce food intake partly depends on 5-HT2C receptors

Behavioral effects of drugs of abuseMost drugs of abuse directly or indirectly enhance

DA‘Ro60-0175’ reduced reinstatement of cocaine-

seeking behavior (antagonist M100907 reduces ) reduced

attenuated nicotine-induced locomotion, nicotine self-administration

reduced impulsivity found experimentally in rats

Psychoactive effects including ‘detached’ ‘spaced out’, ‘floating’

- Treating nicotine dependence with 5-HT2C receptor agonists may be a more realistic therapeutic objective

Concluding remarksDrug abuse and addiction is a potential therapeutic target for 5-HT2C

receptor agonists, and to further suggest that the mechanisms that contribute to antiaddictive property may similarly contribute to efficacy against obesity

Opportunities to evaluate lorcaserin for smoking cessation and psychostimulant abuse

THANKK YOU