High-throughput screening brings in the crops

DDTVol. 5, No. 12 (Suppl.), 2000

(

HTS supplement

I editorial

bring

ughput screening the crops

Screening

gement of ignorance. Such a

concurrent recording of several detection modes at

provocative statemen

ot amuse our community and, in

the same time, from the same well, increases the

fact, an incredible o~

knowledge does go into each

is the ac

resolution of information obtained and verifies it by

,ctural point of view, screening is

immediately cross-checking the results 1. To utilize the predictive power of such information, the appropriate interpretation has to be in

where serendipi~ meets

place. This comprises a successful combination of statistics, visualization, databases and models - all of

T i m m Jessen EVOTEC BioSystems Schnackenburgallee 114 2 2 5 2 5 Hamburg, Germany tel: + 4 9 40 56081 0 fax: + 4 9 40 56081 222 e-mail: timm.jessen@ evotec.de

V Most of the screens performed in industry involve

which are heavily developed in academia and indus-

an encounter between a known target molecule and

try. Again, the driving force here is efficiency be-

a series of chemical compounds in order to identify

cause, despite the ever-increasing throughput num-

a hit, which is nothing more than a structural match.

bers, the most tin'm- and cost-effective way to create

In a screen, the plethora of molecular interactions is

a drug is immediate and successful prediction based

tested simultaneously, but only the net result is usu-

on solid information.

ally observed by the scientist. Dynamic events, sep-

So, will that determine the fate of screening? Just

aration into ionic and non-ionic interactions and in-

the opposite. We have not even completely arrived at

direct effects of the respective molecular environment

the most simplistic level of predicting the molecular

remain camouflaged under a sole signal identified by

interactions between a structurally known protein

the reader. Hence, in the past, the predictive power

and a compound, although good progress has been

of screens has been limited.

made in ensuring short turn-around times in com-

However, improvements are on the way: the pro-

p o u n d synthesis and screening. Already, however, the

tein structure database is growing exponentially*; the

next level of complexity - a structurally unknown

resolution of chemical space is improving; a variety

target - leaves us with little option but screening to

of devices detecting the different nature of molecular

generate knowledge. Not to speak of cellular target

interactions is appearing, and the number of success

screens, reporter assays, biological specificity issues

stories is increasing. Often, Mother Nature has been

or absorption, distribution, metabolism and excretion

the best guide: most of the screening - evolution -

(ADME) tests like the blood-brain-barrier passage. It

had already been done before the design of new

is the assay design, in combination with the respective

insulins, the development of peptidic antagonists stem-

screening platform, where information is accumu-

ming from the natural ligand, or the exploitation of

lated through a thoughtful combination of molecular

RGD motifs in drug discovery. Iterative crystallization

biology, protein chemistry, library design and interpre-

of target/compound pairs, meanwhile, has also achieved

tation of the obtained data.

several 'home runs' (e.g. HIV protease, interleukin-l-~-

HTS is not challenged by rational drug design -

converting enzyme, carboanhydrase), thereby in-

the former is feeding the latter, whereas the latter is

creasing the level of independence from physiological

reshaping and continuously rejuvenating the former.

interactions. Series of focussed chemical libraries

Good et d. describe a good example of this approach

used in high-throughput screening (HTS) already

in this supplement. The harvest is on, and HTS is

balance the 'millions-of-compounds' approach w h e n

reaping the crops.

it comes to a structurally well known target class or hit optimization. Molecular interactions are now increasingly observed on a molecular level and on- and off-rates are becoming part of primary screens. The

Reference 1 Haupts, U. et d. (2000) Macroscopic versus microscopic fluorescence techniques in (u]tra)-highthroughput screening. DrugDiscov.Today 5 (Suppl. High-

* See the latest version of the PDB database, Stony Brooks.

throughputScreening), 3-9

1359-6446/00/$ - see front matter @2000 Elsevier Science Ltd. All rights reserved. PII: $1471-1931 (00)00063-X

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