receptor modulators (SERMs) aspromising hormone replacementtherapy drugs [10]. Thus, phenomena ofunique signaling profiles dictated byparticular ligands at a given receptor arenot limited to the GPCR family. Suchphenomena seem to be imperative fordrug development and we believe thatdepiction of ligand-selective signalingprofiles should become a key part ofpreclinical drug development.Seemingly, compounds exhibitingselective signaling profiles would bemore likely to exhibit reduceddesensitization and fewer side-effects,making them superior candidates forfurther drug development.

References1 Milligan, G. (2003) High-content assays for

ligand regulation of G-protein-coupled

receptors. Drug Discov. Today, 8, 579–5852 Kenakin, T.P. (2003). The secret lives of

GPCRs. Drug Discov. Today 15, 6743 Fisher, A. et al. (1993) Selective signaling via

unique M1 muscarinic agonists. Ann. N. Y.Acad. Sci. 695, 300–303

4 Gurwitz, D. et al. (1994) Discrete activationof transduction pathways associated withacetylcholine m1 receptor by severalmuscarinic ligands. Eur. J. Pharmacol. 267,21–31

5 Haring, R. et al. (1994). Amyloid precursorprotein secretion via muscarinic receptors:reduced desensitization using the M1-selective agonist AF102B. Biochem. Biophys.Res. Commun. 203, 652–658

6 Gurwitz, D. et al. (1995) NGF-dependentneurotrophic-like effects of AF102B, an M1muscarinic agonist, in PC12M1 cells.Neuroreport 6, 485–488

7 Sadot, E. et al. (1996) Activation of m1muscarinic acetylcholine receptor regulatestau phosphorylation in transfected PC12cells. J. Neurochem. 66, 877–880

8 Gether, U. et al. (1995) Fluorescent labeling of purified beta 2 adrenergic

receptor. Evidence for ligand-specificconformational changes. J. Biol. Chem. 270,28268–28275

9 Kukkonen, J.P. et al. (1998) Ligand- andsubtype-selective coupling of human alpha-2adrenoceptors to Ca++ elevation in Chinesehamster ovary cells. J. Pharmacol. Exp. Ther.287, 667–671

10 Kuiper, G.G. et al. (1999) Estrogen receptorand the SERM concept. J. Endocrinol. Invest.122, 594–603

David GurwitzDepartment of Human Genetics and

Molecular MedicineSackler Faculty of Medicine

Tel-Aviv University Tel-Aviv, 69978 Israel

Rachel HaringD-Pharm Ltd

Kiryat Weizmann Science ParkP.O. Box 2313

Rehovot, 76123 Israel

The value of HTS to the drug discoveryarena was debated widely at the Societyfor Biomolecular Screening (SBS) 9thAnnual Conference and Exhibition, inPortland, OR, USA, (21–25 September2003). The solution could lie, in part, in the diversity of SBS sessions beyondtraditional HTS single-point assaytechnology.

As Jeff Pasley from Wyeth (http://www.wyeth.com) discussed in a session titledPoint/Counterpoint: Is HTS Worth theCost?, HTS is moving beyond activityassays into the ADME arena fordetermination of compoundcharacteristics in vitro. However, ascounter proponent Mel Reichman(drughunter@aol.com) added, HTS ismore a commodity in the rapidlyevolving oligopoly pharmaceuticaldiscovery market. With the low barrier

to entry, many academic institutions are now implementing HTS to protecttheir target intellectual property (seehttp://iccb.med.harvard.edu/screening/index.htm).

Furthering HTSWithin small molecule discovery atmany pharmaceutical companies, HTSis now being supplemented anditeratively used with a variety of new methodologies, includingcomputational modelling of compoundactivity, data quality, systems biologyand mechanisms of action at thecellular and organism level. HTS isevolving beyond a search for a needlein a haystack to become a generic,efficient method for testing ahypothesis. Screening assay data isbeing quantified, both in range and

quality, so all results, both negative and positive, can be used to betterunderstand the target, compoundselectivity and the systems biologyunderlying the in vivo therapeuticinteraction.

The SBS sessions investigated twomajor avenues:• A better understanding of systems

biology in order to more accurately

select and screen the drugable

therapeutically relevant targets

• A more efficient selection of compounds

that will be potent against the target as

well as readily bioavailable as an oral

therapeutic.

Meeting highlights• Systems biology for increased

understanding of physiology and target

identification

DDT Vol. 8, No. 24 December 2003 updateconference

1359-6446/03/$ – see front matter ©2003 Elsevier Science Ltd. All rights reserved. PII: S1359-6446(03)02911-8 1109www.drugdiscoverytoday.com

The language of screening evolvesDouglas Drake, IDBS, 1900 Powell Street, Suite 1070, Emeryville, CA 94608, USA; tel: +1 510 596 0780, e-mail: ddrake@id-bs.com, web: http://www.id-bs.com

• High Content Screening (HCS) for a

more mechanistic approach to activity

screening

• Ion channel targets and screening

methodologies

• Focused compound libraries and

scaffolds for selective screening,

‘lead-likeness’ and QSAR for predictive

properties

• Data mining/effective data

QC/quantifying false negatives and false

positives for better selectivity screening.

Each of the SBS keynote speakers,Roger Perlmutter of Amgen (http://www.amgen.com), Christopher Lipinski,formerly of Pfizer (http://www.pfizer.com), and Leroy Hood of the Institutefor Systems Biology (http://www.systemsbiology.org), spoke of the needfor a deeper understanding of humansystems biology, both to identifydrugable therapeutic targets as well as to deliver effective therapeuticssystematically. Despite the influx ofgene data, determining the role eachgene might play in systems biology andin a targeted disease is an unmetchallenge.

Targeting obesityAs Perlmutter described in his keynoteaddress, Amgen’s development ofLeptin (see http://whyfiles.org/051fat_fixes/leptin.html) as atherapeutic, initially based on the studyof target in an animal obesity model,has resulted in treatment for only asmall group of the targeted humanpopulation suffering from obesity.Often, as illustrated by the cox-2receptor, a target first identified in onearea of therapeutic research(inflammation and pain), could havetherapeutic indications in a completelyunrelated medical area (cancer) [1].

Arthur Sands of LexiconPharmaceuticals (http://www.lexgen.com/pharma/) discussed this aspart of Lexicon’s strategy to use its geneknockout technology to map truephysiological response: very few of the

physiological predictive models basedupon gene family and sequence areaccurate [2]. It is more effective forLexicon to observe physiology via thephenotype of its knockout animals andthen release the target to theappropriate therapeutic research forfurther investigation than to rely oncurrent predictive physiological modelsbased on gene family and sequence.Leroy Hood is essentially taking thesame approach at the Institute ofSystems Biology, modelling physiologyas a feedback-regulated system fromgene to protein to cellular andorganism function.

It is clear that a single-point HTSactivity assay does not model an in vivoresponse or the logic of the cellularevent within its natural system.However, as Laszlo Urban of Novartis(http://www.novartis.com) illustrated,use of HTS methodology to develop an early preclinical profile of thecompound via in vitro screens forabsorption, metabolism and toxicologycan reduce expensive clinicaldevelopment time and risk. This processhelps to benchmark not only acompound’s targeted activity but alsoits drugability in vivo before it is evertested in the clinic. Part of the HTS-based approach to compound profilingis an effort to understand variabilitywithin screening data, so that bothpositive and negative data are trulyselective. As Leo Bleicher of Merck(http://www.merck.com) and othersillustrated, the data can then be minedfor promiscuous scaffolds and cross-reactive species.

Investigating target responseAnother theme prevalent at SBS wasrenewed interest in HCS and othermulti-parameter measurement methodsfor investigation of target response inthe context of the cellular system. HCSis increasingly useful for targetvalidation and mechanism of actionstudies, ensuring that a hit candidate is

selected based not only on an order ofmagnitude over background, but alsohighly selective, target-specific activity.Perhaps to the chagrin of the earlyleaders in HCS technology, the price forthese systems has become competitivebut is now both more affordable forand applicable to broader areas oftherapeutic research. Managing thedata produced by these systems is still achallenge as many of the vendors try togo it alone, rather than integrate withdata management systems already inplace and in use among theircustomers.

Ion channels have become asignificant target therapeutic area in thefew years since their discovery. SBSincluded a session on ‘Advances in IonChannel Technology’ just weeks beforethe 2003 Chemistry Nobel Prize wasawarded to biochemists Peter Agre ofJohns Hopkins University (http://www.jhu.edu) and Roderick MacKinnon ofRockefeller University (http://www.rockefeller.edu) ‘for discoveriesconcerning channels in cell membranes’.The primary challenge for drugdiscovery is how to mimic the complexphysiological environment of ionchannels in an HTS format. Ionchannels might not yet fit well into ahomogenous plate-based assay formatbut they represent 5% of all moleculartargets. There are several systems fordirectly measuring ion-flux, and thesewill only get better and more cost-effective.

The reality of virtual screeningA corollary to the systems biologyemphasis at SBS was a focus ondeveloping effective therapeutics thatwork within systems effectively becauseof good ADME characteristics, targetspecificity, minimal drug–druginteractions and minimal side effects.

For therapeutically relevant enzymessuch as kinases and phosphatases, highthroughput crystallography and NMRhave become extremely powerful tools

update conference DDT Vol. 8, No. 24 December 2003

1110 www.drugdiscoverytoday.com

for modelling structure, bindingdomains and protein–ligandinteractions.

Virtual screening has developedbeyond a buzzword to a constructivereality in drug discovery, as illustratedby Steve Muchmore of AbbottLaboratories (http://www.abbott.com).These techniques might have limitedsuccess for targets such as GPCRs andother membrane-bound receptors,because of the lipid bilayer that theyspan. However, using the concept ofprivileged scaffolds [3], Aventis, BMSand Vertex have been able to focustheir compound screens around target-selective compound scaffolds. GilbertRishton of Amgen has identified ‘lead-likeness’ [4] physicochemical propertiesto preselect compounds for activescreening. The outcome is that thecompounds identified for HTS activityscreening have been directed, orenriched, for the target or for both

‘lead-like’ and ‘drug-like’physicochemical properties.

The final and perhaps most importantdiscussion concentrated on how toleverage more value from screeningdata. By understanding the noise withinan assay, one can more readily compareactivity across different screens,regardless of format, or whetherbiochemical or biological. One can thenrecognise cross-reactive or promiscuouscompounds and scaffolds that would beproblematic for further development,and focus only on the compounds thatare truly active and selective for thetarget of interest [5].

To conclude, the data is the mostimportant factor and the basis fromwhich all our future drug discoverieswill be made. What SBS concluded isthat we need more information, anincreased understanding of systemsbiology and improved methods ofdelivering an effective therapeutic to

that biological system. In order to dothis, our efforts and data must beintegrated and, as Christopher Lipinskiformerly of Pfizer concluded, thelanguage and culture of chemistry andbiology made increasingly morecommon.

References1 Kolata, G. (2000) Serendipity and hope in

war on cancer. New York Times, 18 January, F12 Zambrowicz, B.P. et al. (2003) Knockouts

model the 100 best-selling drugs – will theymodel the next 100? Nat. Rev. Drug Discov. 2,38–51

3 Mason, J.S. et al. (1999) New 4-pointpharmacophore method for molecularsimilarity and diversity applications:overview of the method and applications,including a novel approach to the design ofcombinatorial libraries containing privilegedsubstructures. J. Med. Chem. 42, 3251–3264

4 Rishton, G.M. (2003) Non-lead-likeness andlead-likeness in biochemical screening. DrugDiscov. Today 8, 86–96

5 Rishton, G.M. (1997) Reactive compoundsand in vitro false positives in HTS. DrugDiscov. Today 2, 382–384

DDT Vol. 8, No. 24 December 2003 updateconference

1111www.drugdiscoverytoday.com

Contributions to Drug Discovery Today

Drug Discovery Today publishes topical information on all aspects of drug discovery – molecular targets, lead identifi-cation, lead optimization and associated technologies, drug delivery, gene therapy, vaccine development and clinicaltrials – together with overviews of the current status of compound classes and approaches in specific therapeutic areasor disease states. Areas of pharmaceutical development that relate to the potential and viability of drug candidates arealso included, as are those relating to the strategic, organizational and logistic issues underlying pharmaceutical R&D.Authors should aim for topicality rather than comprehensive coverage. Ultimately, articles should improve the reader’sunderstanding of the field addressed and should therefore assist in the increasingly important decision-makingprocesses for which drug discovery and development scientists are responsible.

If you would like to contribute to the Reviews, Monitor or Editorial sections of Drug Discovery Today in the future,please submit your proposals (a one page outline summarizing the proposed article) to: Dr Steve Carney, Editor (e-mail: s.carney@elsevier.com). Completed manuscripts will not be considered. If you would like to contribute to theUpdate section, please submit your proposals to: Dr Joanne Clough, News Editor (e-mail: j.clough@elsevier.com).

Please note that publication of Review articles is subject to satisfactory expert peer and editorial review. The publi-cation of Update and Editorial articles is subject to satisfactory editorial review. In addition, personal perspectivespublished in Drug Discovery Today do not represent the view of the journal or its editorial staff